RET c.2410G>A, p.Val804Met

Reasoning

PS3 is met at strong strength. Multiple independent, variant-specific functional studies support a damaging gain-of-function effect for RET p.Val804Met. In NIH-3T3 focus-formation assays, V804M alone produced 9 transformed foci per microgram of transfected DNA, and the study reported that V804M was activating in both RET isoforms; RET phosphorylation and transformation were also assessed with appropriate wild-type, ligand, and inhibitor contexts (PMID:17047083). Independent recombinant RET kinase and cell-based assays showed that V804M altered kinase inhibitor response relative to wild-type RET, with resistance to SU5416 and preserved mutant RET phosphorylation (PMID:17032739). A further independent study used purified kinase-domain and cell-based autophosphorylation assays comparing wild-type RET and V804M and demonstrated variant-specific pharmacologic behavior (PMID:32923848). The strongest evidence is the direct V804M-alone transformation result and concordant biochemical/cell-based evidence from independent studies; the tandem V804M/E805K results were not used to establish PS3 for V804M alone.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• Carlson et al. 2006 (PMID:17047083), Results, ‘The V804M/E805K tandem mutations are biologically active and transform cells’: NIH-3T3 focus-formation assays found 9 transformed foci per microgram for V804M alone, and the paper states, ‘Additionally, the V804M mutation is activating in both isoforms.’
• Carlomagno et al. 2006 (PMID:17032739), Results, ‘Activity of SU5416 on mutant RET’ (Fig. 8): recombinant RET V804M kinase and NIH-3T3 cells expressing RET V804M showed resistance to SU5416, with no 50% inhibition up to 30 mM and no inhibition of mutant RET phosphorylation.
• Subbiah et al. 2020 (PMID:32923848), Case Report/Results, Fig. 2 and Fig. 3: purified RET kinase-domain and cell-based autophosphorylation assays compared wild-type RET and RET V804M and showed variant-specific inhibitor-response differences; the clinical report also explicitly identifies hereditary RET V804M.
• The tandem V804M/E805K findings in PMID:17047083 were not independently attributed to V804M when evaluating PS3; only the reported V804M-alone transformation result and concordant variant-specific assays were used.

Sources

Reasoning

The variant is a missense substitution, NP_066124.1:p.(Val804Met), so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3 in this situation. REVEL is 0.716, which meets the generic PP3 supporting threshold of >=0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). BayesDel has no established generic ACMG-strength calibration and is not used. Therefore PP3 is met at supporting strength.

Rule

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) ... Missense variant -> REVEL only.

Evidence considered

• Local REVEL predictor lookup for NM_020975.6:c.2410G>A / NP_066124.1:p.(Val804Met): REVEL score 0.716.
• ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997): generic PP3 supporting threshold is >=0.644; the observed score meets it.
• SpliceAI max delta 0.011 was not counted because this is a missense variant and the governing path is REVEL only; BayesDel was not counted because no generic ACMG-strength calibration is established.

Sources

Reasoning

The variant is RET c.2410G>A, p.Val804Met. The reviewed literature documents this exact nucleotide and amino-acid substitution, including the GTG-to-ATG change, but no distinct nucleotide change producing the same Val-to-Met substitution at codon 804 was identified. Therefore the requirement for a previously established pathogenic variant with the same amino-acid change regardless of nucleotide change is not met. The available functional and clinical reports concern the exact variant and cannot by themselves establish PS1.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.

Evidence considered

• PMID:17047083 reports RET V804M as a germline mutation and evaluates the exact V804M substitution.
• PMID:18299477 explicitly reports c.2410G>A (p.V804M) in exon 14.
• PMID:20719260 identifies the RET V804M mutation and cites the GTG-to-ATG change; these sources document the exact allele rather than an alternate nucleotide encoding the same amino-acid change.

Sources

Reasoning

Applied the generic ACMG/AMP PS4 definition and threshold: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." The governing note requires relative risk or odds ratio >5.0 with a confidence interval that does not include 1.0. The literature_pass PS4 candidates were checked against available abstracts/full-text extracts: PMID:18299477 is a single-patient report, PMID:20719260 is an observational family report, and PMID:20664475 is a general guideline that does not identify c.2410G>A/p.V804M. None reports affected-versus-unaffected control counts, a case frequency, or a matched-ancestry case-control comparison, so no OR or 95% CI can be computed. gnomAD provides population control frequency (AF 0.00012208 in v4.1; 0.000136393 in v2.1) but no affected-case frequency; therefore the required comparison is not met.

Rule

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.

Evidence considered

• PMID:18299477 reports one affected individual with RET c.2410G>A/p.V804M and describes incomplete penetrance; it is not a case-control study.
• PMID:20719260 reports a 107-member V804M family but provides no unaffected-control comparison or case-control counts.
• PMID:20664475 discusses RET codon 804 risk generally and does not identify this exact variant or provide case-control counts.
• gnomAD v4.1 reports p.V804M in 196/1,605,504 alleles (AF 0.00012208); this is a population control frequency without an affected-case numerator.
• The literature_pass PS4 candidate list was verified against the available abstract/full-text extracts before concluding that qualifying case-control evidence was absent.

Still missing

• A case-control cohort or affected-case frequency with a comparable control denominator is needed to calculate an OR/RR and 95% CI.

Sources

Reasoning

PM2 is not met under the generic default source selection. Generic rules do not specify a non-cancer or exome-only source, so the all-comers gnomAD datasets are used. The applicable gnomAD v2.1 grpmax FAF is 0.00012796 and the gnomAD v4.1 grpmax FAF is 0.00010561; both exceed the generic PM2 supporting threshold of <=0.0001. The variant is therefore present at a frequency just above the threshold rather than absent or at an extremely low qualifying frequency. Non-cancer subsets are lower (gnomAD v2.1 exomes grpmax FAF 0.00008046 and gnomAD v3.1 genomes grpmax FAF 0.00007911), but they are not the governing source under the generic rule because no VCEP or source restriction requires them.

Rule

PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)

Evidence considered

• Generic source selection uses all-comers gnomAD because no VCEP rule specifies a non-cancer or exome-only population source.
• gnomAD v2.1 all-comers: grpmax FAF 0.00012796, AF 0.000136393 from 36/263944 alleles, homozygotes 0.
• gnomAD v4.1 all-comers: grpmax FAF 0.00010561, AF 0.00012208 from 196/1605504 alleles, homozygotes 0.
• For context only, the non-cancer subsets report lower filtering frequencies: gnomAD v2.1 non-cancer exomes grpmax FAF 0.00008046 and gnomAD v3.1 non-cancer genomes grpmax FAF 0.00007911; these do not control the generic assessment here.
• The filtering allele frequency, rather than a population point estimate, was used for the threshold comparison.

Sources

Reasoning

The reviewed evidence identifies another substitution at residue 804, V804L, in the context of acquired inhibitor resistance and structural modeling, but does not establish V804L as a pathogenic germline disease variant. No different missense change at Val804 with an established pathogenic classification was identified. The exact V804M variant itself is not a PM5 comparator for this criterion.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.

Evidence considered

• PMID:32923848 reports V804L and V804M as RET gatekeeper resistance substitutions and provides preclinical inhibitor assays, but does not establish V804L as a pathogenic germline disease variant.
• PMID:17047083 concerns the exact V804M substitution and therefore is not a different-missense comparator.
• ClinVar records the exact c.2410G>A (p.Val804Met) allele; the reviewed record does not establish a different pathogenic missense allele at residue 804.

Sources

Reasoning

The governing PP5 definition concerns a reputable recent pathogenic report when independent evaluation is unavailable. For this exact variant, ClinVar contains Pathogenic/Likely pathogenic laboratory submissions, but the submission audit records zero expert-panel submissions and zero usable criterion leads; the review status is criteria provided, multiple submitters, no conflicts, not an expert-panel assertion. Under the specified generic PP5 restriction, ordinary laboratory submissions, aggregate labels, and non-expert assertions do not trigger PP5.

Rule

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar exact-variant record for NM_020975.6:c.2410G>A/p.Val804Met reports Pathogenic/Likely pathogenic classifications with review status criteria provided, multiple submitters, no conflicts.
• The ClinVar submission audit records expert_panel_submissions = 0 and usable_for_criterion_leads = 0; therefore the record is not an expert-panel classification eligible for PP5 under the specified rule.

Sources

Reasoning

BA1 is not met. Under the generic default, BA1 requires a filtering allele frequency (grpmax FAF) of at least 0.05. The applicable all-comers gnomAD values are far below this threshold: grpmax FAF is 0.00012796 in gnomAD v2.1 and 0.00010561 in gnomAD v4.1. The highest population point estimates are not used for BA1, and neither all-comers dataset provides a frequency remotely approaching 5%. The variant has a strong disease association and pathogenic ClinVar consensus, further requiring caution against a stand-alone benign call from a default frequency threshold.

Rule

BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)

Evidence considered

• gnomAD v2.1 all-comers: AF 0.000136393 from 36/263944 alleles, homozygotes 0, grpmax FAF 0.00012796.
• gnomAD v4.1 all-comers: AF 0.00012208 from 196/1605504 alleles, homozygotes 0, grpmax FAF 0.00010561.
• For BA1 and BS1, the filtering allele frequency (grpmax FAF), not the population point estimate, was used; the observed population sample sizes exceed 2000 alleles for the relevant broad populations.
• The variant is associated with hereditary RET disease and has a pathogenic/likely pathogenic ClinVar consensus; therefore a stand-alone benign interpretation from a default frequency threshold would be inappropriate even if a higher frequency had been observed.

Sources

Reasoning

BS1 is not met. The generic default is allele frequency >=0.01, but the required filtering allele frequency is only 0.00012796 in gnomAD v2.1 and 0.00010561 in gnomAD v4.1, both substantially below 1%. The variant is associated with a late-onset, variably penetrant RET disorder, so a maximum-credible-frequency calculation would be needed before using a lower or ancestry-specific benign threshold; no such calculation is necessary here because the observed FAF is already well below the generic default. The highest population point estimate is not used for BS1.

Rule

BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)

Evidence considered

• gnomAD v2.1 all-comers: grpmax FAF 0.00012796; total AF 0.000136393 from 36/263944 alleles.
• gnomAD v4.1 all-comers: grpmax FAF 0.00010561; total AF 0.00012208 from 196/1605504 alleles.
• The grpmax FAF rather than the highest population AF was used, consistent with the ClinGen SVI/Ghosh et al. filtering-frequency guidance supplied for this interpretation.
• Published clinical evidence describes RET p.Val804Met as a low, variably penetrant, late-onset disease-associated variant; this means the generic 1% value should not be treated as universally applicable without a maximum-credible-frequency calculation, but the observed FAF remains far below it.

Sources

Reasoning

BS3 is not met. No well-established functional study in the reviewed evidence demonstrates that RET p.Val804Met has no damaging effect on protein function or splicing. Instead, the available variant-specific studies show activating transformation, altered RET kinase behavior, resistance to kinase inhibition, and preserved mutant RET phosphorylation, which are inconsistent with a benign functional effect (PMID:17047083; PMID:17032739; PMID:32923848).

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• PMID:17047083 reports V804M-alone transforming activity and states that V804M is activating in both RET isoforms, contrary to a no-damage result.
• PMID:17032739 reports RET V804M resistance to SU5416 and persistent mutant RET phosphorylation in recombinant kinase and cell-based assays, contrary to a normal-function result.
• PMID:32923848 reports variant-specific biochemical and cell-based RET V804M behavior relative to wild-type RET, without demonstrating normal protein function or normal splicing.

Sources

Reasoning

The available gene and variant evidence supports an activating missense disease mechanism for RET rather than a disorder caused primarily by truncating variants. RET V804M is experimentally activating, and curated variant context describes RET alterations as gain-of-function. Thus the premise that primarily truncating variants are known to cause disease is not supported for this gene in the reviewed evidence.

Rule

Missense variant in a gene for which primarily truncating variants are known to cause disease.

Evidence considered

• PMID:17047083 reports that RET V804M is activating and evaluates its transformation and phosphorylation effects.
• OncoKB characterizes RET V804M biological effect as gain-of-function and labels it oncogenic.
• ClinVar includes the exact RET missense allele among multiple pathogenic submissions, consistent with missense disease mechanism rather than a primarily truncating mechanism.

Sources

Reasoning

The variant is a missense substitution, so the governing generic rule selects the REVEL path only; SpliceAI is not used for BP4 in this situation. REVEL is 0.716, which is above the generic BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so it does not support no impact. The SpliceAI max delta of 0.011 cannot substitute for the applicable REVEL result, and BayesDel has no established generic ACMG-strength calibration. Therefore BP4 is not met.

Rule

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only.

Evidence considered

• Local REVEL predictor lookup for NM_020975.6:c.2410G>A / NP_066124.1:p.(Val804Met): REVEL score 0.716.
• ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997): generic BP4 supporting threshold is <=0.29; the observed score does not meet it.
• SpliceAI max delta 0.011 was not used because this missense variant must be evaluated through the REVEL-only path; BayesDel was not used because no generic ACMG-strength calibration is established.

Sources

Reasoning

The governing BP6 definition concerns a reputable recent benign report when independent evaluation is unavailable. The exact-variant ClinVar record contains Pathogenic/Likely pathogenic laboratory submissions and no benign expert-panel classification; the submission audit records zero expert-panel submissions. Ordinary laboratory submissions, aggregate labels, and non-expert assertions do not trigger BP6, and no qualifying benign expert-panel assertion is present.

Rule

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar exact-variant record reports Pathogenic/Likely pathogenic laboratory submissions with no benign expert-panel assertion.
• The ClinVar submission audit records expert_panel_submissions = 0; therefore no qualifying benign expert-panel source supports BP6 under the specified rule.

Sources

Reasoning

The available record does not establish a de novo occurrence in a proband with confirmed maternity and paternity. One ClinVar submission labels the origin as de novo, but no parental test results, maternity confirmation, paternity confirmation, phenotype details, or source-level case documentation are provided. Therefore, PS2 cannot be assessed.

Rule

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Evidence considered

• ClinVar variation 37102 includes one submission with origin recorded as "de novo", but the case-level parental testing and maternity/paternity confirmation needed for PS2 are not reported.
• The available variant-specific literature describes inherited RET V804M families and does not document a confirmed de novo occurrence for this case.

Still missing

• Documented proband phenotype consistent with the RET-related disease.
• Variant testing results for both biological parents.
• Confirmed maternity and paternity, with exclusion of sample or parentage errors.
• Documented absence of relevant family history.

Sources

Reasoning

RET p.Val804Met lies in the RET tyrosine-kinase domain at the Val804 gatekeeper/ATP-binding-site region, and functional literature describes this position as an active-site gatekeeper. However, the generic PM1 rule requires a mutational hotspot or critical, well-established functional domain without benign variation, and the available evidence does not provide a comprehensive assessment of benign variation across the relevant domain or establish that the domain is free of benign variation. The isolated COSMIC occurrence and lack of a statistically significant hotspot do not complete the generic PM1 requirement.

Rule

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

Evidence considered

• PMID:17047083 places Val804 at the RET kinase active-site gatekeeper and hydrophobic hinge region and describes V804M as activating in both RET isoforms.
• PMID:32923848 describes V804 as a RET kinase-domain gatekeeper residue and evaluates V804L/V804M resistance mutations.
• Cancer Hotspots reports that this variant does not lie in a statistically significant hotspot; COSMIC reports one somatic occurrence, which is insufficient to establish the generic PM1 hotspot/domain requirement without benign-variation assessment.

Still missing

• A gene- and domain-level assessment demonstrating absence of benign variation in the relevant RET kinase-domain region is required.

Sources

Reasoning

A ClinVar submission records the variant origin as de novo, but the available evidence does not provide a documented proband, phenotype consistency, parental testing context, or a case report supporting an assumed de novo event. The submission metadata alone is insufficient to assess PM6.

Rule

Assumed de novo, but without confirmation of paternity and maternity.

Evidence considered

• ClinVar variation 37102 includes one submission with origin recorded as "de novo", but no supporting parental test details or source-level clinical documentation are available.
• The available paper extract for PMID:20719260 concerns an inherited 107-member RET V804M family rather than an assumed de novo occurrence.

Still missing

• A source-level clinical report identifying the proband and disease phenotype.
• Evidence that the variant was absent from the tested parent or parents.
• Documentation of the testing and family-history context supporting an assumed de novo event.

Sources

Reasoning

PMID:20719260 reports a 107-member family carrying RET V804M and describes affected carriers, including medullary thyroid carcinoma, but the available report does not provide a complete genotype-by-phenotype segregation table or a count of informative affected and unaffected meioses. The evidence indicates familial occurrence but is insufficient to assign PP1 strength under the supplied rule.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.

Evidence considered

• Shifrin et al., PMID:20719260, reports a 107-member family with germline RET V804M; the response states that family members were tested with calcitonin assays and RET testing and describes a first-generation member with extensive metastatic medullary thyroid carcinoma.
• The same report notes incomplete follow-up for recurrence and does not present a complete segregation count or pedigree sufficient to quantify co-segregation strength.

Still missing

• A pedigree or table identifying each tested family member's genotype and phenotype.
• The number of affected variant-positive relatives and informative meioses.
• The number and phenotype status of tested variant-negative relatives.
• Phenotype definitions and age-dependent penetrance considerations for each relative.

Sources

Reasoning

RET has well-documented disease-associated activating missense variants, including p.Val804Met, but the available case evidence does not establish the gene-level combination required for PP2: a low rate of benign missense variation together with missense variants being a common disease mechanism. Variant-level rarity in gnomAD and pathogenic submissions for this allele cannot substitute for a gene-wide benign-missense rate assessment.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

Evidence considered

• PMID:17047083 demonstrates activating biology for RET V804M and supports that missense activation is a disease mechanism in RET.
• OncoKB describes RET V804M as gain-of-function and oncogenic.
• gnomAD v4.1 reports the variant at AF 0.00012208, and ClinVar reports multiple pathogenic submissions; neither provides the required gene-wide benign-missense rate.

Still missing

• A gene-level analysis of benign missense variation and the relative prevalence of missense disease mechanism is required.

Sources

Reasoning

The governing rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available case evidence identifies RET p.V804M but does not provide the current patient's phenotype or family history in sufficient detail to judge specificity; phenotypes reported in separate publications cannot substitute for this patient's clinical presentation.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Evidence considered

• The case materials provide variant identity and literature observations but no sufficiently detailed current-patient phenotype or family-history description for PP4 assessment.

Still missing

• Detailed current-patient phenotype and family history, including the suspected disease diagnosis and competing etiologies, are needed.

Reasoning

BS2 is not assessed. The available population records show zero homozygotes in gnomAD v2.1 and v4.1, but they do not document an individual-level healthy adult observation with verified age, phenotype, and genotype. For this autosomal dominant, late-onset and variably penetrant RET disorder, absence of homozygotes is not evidence for BS2, and a heterozygous carrier in an unphenotyped population database cannot be treated as a healthy adult with expected full early-age penetrance. A qualifying healthy adult observation or an appropriately documented penetrance assessment is required.

Rule

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Evidence considered

• gnomAD v2.1 reports 0 homozygotes among 263944 alleles; gnomAD v4.1 reports 0 homozygotes among 1605504 alleles.
• The population records do not provide verified individual ages, clinical examinations, or phenotype-negative status for carriers.
• RET p.Val804Met is described in the literature as low and variably penetrant with late-onset disease, so an unphenotyped population carrier cannot satisfy the BS2 requirement for a healthy adult with full penetrance expected at an early age.

Still missing

• No individual-level healthy adult carrier with verified age, phenotype, and genotype was identified.

Sources

Reasoning

The available evidence does not document affected relatives who lack RET V804M, nor does it provide an informative family segregation analysis demonstrating non-segregation. The presence of variable and age-dependent expression in RET V804M carriers also prevents treating incomplete disease observation alone as lack of segregation.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• PMID:20719260 describes a familial RET V804M cohort and variable clinical findings, but does not report affected non-carriers or a formal non-segregation analysis.
• The report describes follow-up of asymptomatic carriers and incomplete follow-up, so absence of disease in a carrier is not evidence of BS4.

Still missing

• Genotyped affected relatives shown to be negative for RET V804M.
• A family pedigree with phenotype and genotype for informative relatives.
• Assessment of age-dependent penetrance and possible phenocopies before assigning non-segregation.

Sources

Reasoning

Cranston et al. directly confirmed that RET V804M and E805K were present in cis in a MEN2B proband, and reported that the tandem lesion transformed cells. However, the report does not establish E805K as an independently pathogenic variant: the transforming effect was synergistic in combination, while E805K alone showed weak or context-dependent activity. No separate, independently classified pathogenic variant in cis or pathogenic variant in trans was documented for this case. Therefore, the cis observation cannot be assigned BP2 without resolving whether E805K independently satisfies the required pathogenic-variant condition.

Rule

BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• Cranston et al. 2006 (PMID:17047083), Abstract: the patient harbored a novel pair of germline missense mutations in cis at codons 804 and 805.
• Cranston et al. 2006 (PMID:17047083), Results: DNA sequencing and subcloning confirmed V804M and E805K in the cis configuration in the MEN2B proband.
• Cranston et al. 2006 (PMID:17047083), functional results: V804M/E805K produced 42 transformed foci per microgram in the long RET isoform versus 9 for V804M and 8 for E805K, and the authors described the combination as synergistic; this does not independently establish E805K as pathogenic.

Still missing

• Independent evidence or classification establishing E805K as a pathogenic RET variant is needed to apply the BP2 cis pathway.

Sources

Reasoning

The governing BP5 definition requires the variant to be found in a case with an alternate molecular basis for disease. The available case materials and reviewed variant-specific reports do not document an alternate molecular diagnosis for the patient; absence of such documentation is insufficient to establish BP5 or to exclude it definitively.

Rule

Variant found in a case with an alternate molecular basis for disease.

Evidence considered

• No case-level alternate molecular diagnosis or competing pathogenic variant is documented in the supplied evidence.

Still missing

• An explicit alternate molecular diagnosis in the same case, with supporting genetic or molecular test results, is needed.