MUTYH c.1258C>A, p.Leu420Met

Reasoning

BS3 is met at supporting strength. PMID:25820570 directly evaluated p.L420M in a biologically relevant MUTYH base-excision-repair complementation assay using MutY-deficient E. coli, with nine independent cultures, empty-vector and wild-type controls, and follow-up protein expression and nuclear-localization studies in HCT116 human colon cancer cells. The assay classified p.L420M as functionally retained, defined as a rifampicin-resistant mutation rate less than 1.7-fold above wild type. The result supports no damaging effect on MUTYH protein function, but the assay is a heterologous bacterial complementation model and the authors describe the cutoffs as tentative, so the evidence is not calibrated above supporting strength.

Rule

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

Evidence considered

• Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain, Results: p.L420M was categorized as functionally retained.
• The assay measured MUTYH base-excision-repair activity through rifampicin-resistant mutation rates in MutY-deficient E. coli and used nine independent overnight cultures.
• Wild-type MUTYH reduced the mutation rate to 9.67/10^8 compared with 137/10^8 for the empty-vector control, demonstrating assay complementation and biological relevance.
• The study's retained-function threshold was a mutation rate less than 1.7-fold higher than wild type; p.L420M met that threshold.
• HCT116 human colon cancer cell experiments showed minimal variant-related protein-level differences and mainly nuclear localization for all tested variants, including the study's p.L420M construct.

Still missing

• Independent replication in a validated clinical diagnostic assay or an orthogonal human-cell functional assay is not documented for p.L420M.

Sources

Reasoning

PS3 is not met. PMID:25820570 evaluated the exact protein substitution p.L420M corresponding to NM_001128425.2:c.1258C>A in a MutY-deficient E. coli complementation assay. The study used nine independent overnight cultures, an empty-vector control, and wild-type MUTYH as a functional control; wild-type MUTYH reduced the rifampicin-resistant mutation rate to 9.67/10^8 versus 137/10^8 with empty vector. p.L420M was classified as functionally retained because its mutation rate was less than 1.7-fold higher than wild type, and it did not show abnormal nuclear localization in HCT116 cells. These results do not support a damaging effect and therefore do not satisfy PS3.

Rule

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

Evidence considered

• Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain, Results: the exact p.L420M variant was categorized as functionally retained.
• The assay included nine independent overnight cultures, an empty-vector control, and wild-type MUTYH; wild type produced 9.67/10^8 rifampicin-resistant mutations versus 137/10^8 with empty vector.
• The study defined functionally retained variants as having a mutation rate less than 1.7-fold higher than wild-type MUTYH; p.L420M was in that category.
• HCT116 expression studies found minimal differences in MUTYH protein levels, and all 47 variants showed mainly nuclear localization similar to wild type.

Sources

Reasoning

PM2 is not met under the supplied generic SVI threshold. The variant is present at clearly more than the <=0.0001 supporting threshold in every relevant dataset: gnomAD v2.1 non-cancer exomes AF 0.000604105 (143/236714), gnomAD v3.1 non-cancer genomes AF 0.000439177 (65/148004), and gnomAD v4.1 all-comers AF 0.000553215 (893/1614202). It is therefore neither absent nor at an extremely low frequency compatible with the supplied PM2 threshold, despite being rare overall.

Rule

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v2.1 non-cancer exomes: AF 0.000604105, 143/236714 exome alleles, 1 homozygote.
• gnomAD v3.1 non-cancer genomes: AF 0.000439177, 65/148004 genome alleles, 0 homozygotes.
• gnomAD v4.1 all-comers: AF 0.000553215, 893/1614202 alleles, 2 homozygotes.
• Generic published calibration threshold supplied for this interpretation: PM2 <=0.0001, SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020; threshold block cites PMID:25741868).

Sources

Reasoning

The variant is a missense SNV, p.(Leu420Met), so the generic missense path applies and REVEL is the only permitted predictor for PP3/BP4. REVEL is 0.45, below the generic PP3 supporting threshold of >=0.644; therefore PP3 is not met. The available SpliceAI max delta of 0.001 is not used because splice prediction is not the applicable path for a missense variant. BayesDel is not used because no generic ACMG-strength calibration is established.

Rule

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).

Evidence considered

• Case consequence: NM_001128425.2:c.1258C>A is a missense SNV producing NP_001121897.1:p.(Leu420Met).
• Local REVEL lookup reports score 0.45 for the variant; the supplied ClinGen SVI calibration gives PP3 supporting at >=0.644, moderate at >=0.773, and strong at >=0.932 (Pejaver et al. 2022, Am J Hum Genet, PMID:36413997).
• SpliceAI max delta 0.001 is not evidence for PP3/BP4 here because the governing generic path assigns missense variants to REVEL only; BayesDel has no established generic ACMG-strength calibration.

Sources

Reasoning

PP5 requires a reputable source to recently report the exact variant as pathogenic when the underlying evidence is unavailable for independent evaluation. The exact-variant ClinVar record has no expert-panel submission and instead contains conflicting ordinary laboratory and non-expert assertions, predominantly likely benign, uncertain significance, or benign. Those assertions cannot trigger PP5 under the supplied generic rule.

Rule

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

Evidence considered

• The exact-variant ClinVar audit reports expert_panel_submissions = 0 and conflicting classifications from ordinary submitters.
• The available ClinVar classifications are not an expert-panel pathogenic or likely-pathogenic assertion, so they do not qualify for PP5.
• No other qualifying reputable exact-variant pathogenic source was identified.

Sources

Reasoning

BA1 is not met. The governing generic threshold is >=0.05, but the relevant filtering frequency is the grpmax FAF, not a population point estimate. The highest applicable grpmax FAF is 0.00152537 in gnomAD v4.1 all-comers, and the older non-cancer/exome-specific gnomAD v2.1 grpmax FAF is 0.00067888; both are below 0.05. The elevated point estimates in Ashkenazi Jewish (gnomAD v2.1 AF 0.00213068 from 21/9856 alleles) and Middle Eastern (gnomAD v4.1 AF 0.00247606 from 15/6058 alleles) do not approach the threshold, and the v3.1 non-cancer maximum point estimate is from HGDP:MOZABITE with only 1/52 alleles, below the required 2000 observed alleles for frequency use. No BA1 stand-alone benign conclusion is supported by the population data.

Rule

Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v4.1 all-comers: AF 0.000553215 (893/1,614,202 alleles; 2 homozygotes), grpmax FAF=0.00152537; the highest observed Middle Eastern point estimate was AF 0.00247606 from 15/6058 alleles.
• gnomAD v2.1 non-cancer exomes: AF 0.000604105 (143/236,714 exome alleles; 1 homozygote), grpmax FAF=0.00067888; the highest observed Ashkenazi Jewish point estimate was AF 0.00213068 from 21/9856 alleles.
• gnomAD v3.1 non-cancer genomes: grpmax FAF=0.00041771; its highest point estimate was HGDP:MOZABITE AF 0.0192308 from only 1/52 alleles, so it does not satisfy the 2000-observed-allele population-size requirement.
• Generic published calibration threshold supplied for this interpretation: BA1 >=0.05, ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868).

Sources

Reasoning

BS1 is not met on the available population-frequency evidence. The generic default threshold is >=0.01, and the required filtering frequency is grpmax FAF. The highest relevant value is 0.00152537 in gnomAD v4.1 all-comers; the non-cancer/exome-specific values are 0.00067888 in gnomAD v2.1 and 0.00041771 in gnomAD v3.1, all below 0.01. The variant is in an autosomal-recessive MUTYH disorder, but no disease prevalence, penetrance, allelic heterogeneity, or maximum-credible-frequency calculation in this case supports a lower gene-specific BS1 threshold. Therefore the observed frequency does not establish that it is greater than expected for the disorder.

Rule

Allele frequency is greater than expected for disorder.

Evidence considered

• gnomAD v4.1 all-comers: grpmax FAF=0.00152537; total AF 0.000553215 from 893/1,614,202 alleles.
• gnomAD v2.1 non-cancer exomes: grpmax FAF=0.00067888; exome AF 0.000604105 from 143/236,714 alleles.
• gnomAD v3.1 non-cancer genomes: grpmax FAF=0.00041771; AF 0.000439177 from 65/148,004 alleles.
• Generic published calibration threshold supplied for this interpretation: BS1 >=0.01; the prompt identifies Whiffin et al. 2017 (PMID:28518168) as the preferred source for a per-gene maximum-credible-frequency derivation.
• The case framework identifies MUTYH-associated polyposis as autosomal recessive, but provides no prevalence, penetrance, allelic-heterogeneity inputs, or gene-specific maximum-credible-frequency calculation that would support applying BS1 below the supplied generic threshold.

Sources

Reasoning

The variant is a missense SNV, p.(Leu420Met), so the generic missense path applies and REVEL is the only permitted predictor for PP3/BP4. REVEL is 0.45, above the generic BP4 supporting threshold of <=0.29 and within the indeterminate gray zone; therefore BP4 is not met. The available SpliceAI max delta of 0.001 is not used because splice prediction is not the applicable path for a missense variant. BayesDel is not used because no generic ACMG-strength calibration is established.

Rule

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)

Evidence considered

• Case consequence: NM_001128425.2:c.1258C>A is a missense SNV producing NP_001121897.1:p.(Leu420Met).
• Local REVEL lookup reports score 0.45 for the variant; the supplied ClinGen SVI calibration gives BP4 supporting at <=0.29, moderate at <=0.183, and strong at <=0.016 (Pejaver et al. 2022, Am J Hum Genet, PMID:36413997).
• REVEL 0.45 is in the generic gray zone, so BP4 is not met and the SpliceAI max delta 0.001 cannot be substituted for the missense path.

Sources

Reasoning

BP6 requires a reputable source to recently report the exact variant as benign when the underlying evidence is unavailable for independent evaluation. The exact-variant ClinVar record has no expert-panel submission and its benign or likely-benign entries are ordinary laboratory, research, or curation assertions, with conflicting classifications also present. Under the supplied generic rule, these non-expert assertions cannot trigger BP6.

Rule

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

Evidence considered

• The exact-variant ClinVar audit reports expert_panel_submissions = 0.
• Benign and likely-benign ClinVar classifications come from ordinary submissions and are accompanied by conflicting uncertain-significance assertions.
• Ordinary laboratory submissions, aggregate labels, and non-expert assertions are excluded from BP6 under the supplied generic rule.

Sources

Reasoning

The variant is NP_001121897.1:p.(Leu420Met), but the available evidence does not establish a previously established pathogenic variant producing the same Leu-to-Met amino-acid change at this codon. ClinVar contains conflicting classifications for the exact variant and no expert-panel pathogenic assertion; the reviewed MUTYH functional paper reports p.L420M as functionally retained rather than as an established pathogenic comparator. A complete pathogenic same-amino-acid comparator search is not documented, so PS1 cannot be determined.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• The case variant is NP_001121897.1:p.(Leu420Met). ClinVar reports conflicting classifications and no expert-panel submission for the exact variant; this is not used as a pathogenic classification.
• Functional Complementation Assay for 47 MUTYH Variants reports p.L420M among variants classified as functionally retained, not as a previously established pathogenic comparator.

Still missing

• A complete search for previously established pathogenic MUTYH Leu-to-Met substitutions at codon 420 is not documented.

Sources

Reasoning

No case-specific evidence documents a de novo occurrence in the proband, confirmed maternity and paternity, disease phenotype, or absence of family history. The available case materials contain no parental genotypes or inheritance analysis; 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

• The case summary identifies MUTYH-associated familial adenomatous polyposis 2 as an autosomal recessive condition but does not provide a proband phenotype, parental testing, or de novo analysis.
• The direct prefetch and VCEP-materials files contain no documented maternal or paternal genotype, confirmed maternity or paternity, or family-history assessment for NM_001128425.2:c.1258C>A.

Still missing

• Proband disease phenotype and diagnostic basis
• Maternal genotype or confirmed maternity
• Paternal genotype or confirmed paternity
• Family history assessment

Sources

Reasoning

Generic ACMG/AMP PS4 requires a statistically significant excess of the variant in affected individuals versus controls, with OR or RR >5.0 and a confidence interval excluding 1.0. The literal threshold comparison is OR/RR > 5.0; because no calculable OR or RR is available, the explicit evaluation is 'OR/RR > 5.0? cannot be evaluated'. The literature packet's PS4 criterion index contains only unverified leads, and packet.ai_classified_papers is empty. The available exact-variant lead reports the p.Leu420Met variant in four individuals with colorectal cancer, but provides no matched unaffected/population control count or case-control frequency suitable for calculating an OR and 95% CI. gnomAD v4.1 shows 893/1,614,202 alleles (AF 0.000553215), but no comparable affected-case numerator and denominator are available. Therefore the required case-control enrichment and statistical threshold cannot be assessed.

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

• ClinVar's exact-variant literature trail contains a lead describing p.Leu420Met in four individuals with colorectal cancer, but this is not accompanied by an unaffected/control count.
• The literature packet's ai_classified_papers list is empty; no already-read paper extraction verifies a case-control comparison for this variant.
• gnomAD v4.1 reports 893/1,614,202 alleles (AF 0.000553215), but no affected-case frequency is available, so an OR and 95% CI cannot be computed from the available evidence.
• The four-case observation alone does not satisfy the PS4 case-control enrichment requirement.

Still missing

• A verified exact-variant affected-case cohort with denominators and matched-ancestry controls is unavailable.
• No calculable OR or RR with a 95% CI was identified.

Sources

Reasoning

The generic PM1 definition requires a mutational hot spot or a critical, well-established functional domain without benign variation. Cancer Hotspots returned no statistically significant hotspot for MUTYH L420. The MUTYH VCEP materials contain no domain-table entry and no released criterion specification, so no authoritative approved domain list or qualifying MUTYH functional-domain boundary is available in this case. The evidence therefore does not permit a complete PM1 determination.

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

• Cancer Hotspots queried MUTYH L420 and returned no statistically significant hotspot.
• The MUTYH VCEP materials identify a CSPEC document but report no released criteria and an empty domain_tables object; therefore no VCEP-authoritative domain list can be applied.

Still missing

• A validated MUTYH critical-domain definition and evidence that codon 420 lies within it are unavailable.
• Evidence that the relevant region lacks benign variation is unavailable.

Sources

Reasoning

PM3 cannot be assessed from the available evidence. MUTYH-associated polyposis is an autosomal recessive disorder, but the case materials do not document an affected proband carrying NM_001128425.2:c.1258C>A together with a pathogenic MUTYH variant, nor do they establish phase by parental or offspring testing. Population homozygote counts and the ClinVar aggregate classification do not establish a pathogenic variant in trans.

Rule

For recessive disorders, detected in trans with a pathogenic variant

Evidence considered

• ClinVar variation 41752 reports conflicting classifications for the queried variant and does not provide an affected-proband observation with a specified pathogenic second MUTYH allele or phase information.
• The CSPEC record identifies MUTYH-associated polyposis as autosomal recessive but has no released criterion specifications; generic ACMG/AMP rules therefore govern this assessment.
• The available population data report homozygotes in gnomAD, but population homozygosity does not establish that the variant is in trans with a pathogenic variant in an affected proband.

Still missing

• Affected-proband-level evidence pairing NM_001128425.2:c.1258C>A with a pathogenic MUTYH variant is absent.
• Parental or offspring testing establishing trans phase is absent.
• The identity and pathogenicity of any second MUTYH allele are not documented.

Sources

Reasoning

The variant is p.Leu420Met. The case's PM5 candidate artifact found no confirmed same-residue comparator and explicitly states that classic same-residue PM5 semantics could not be safely confirmed. The reviewed functional paper discusses p.L420M itself but does not establish a different pathogenic missense substitution at Leu420. PM5 therefore cannot be determined from the documented evidence.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Evidence considered

• The PM5 candidate record reports zero total candidates and zero same-residue candidates and recommends manual review rather than applying PM5.
• The reviewed MUTYH assay paper mentions p.L420M itself but does not report a different pathogenic missense change at residue 420.

Still missing

• A verified pathogenic missense comparator at MUTYH residue Leu420 is not documented.

Sources

Reasoning

No case-specific evidence documents an assumed de novo occurrence in the proband. The available case materials do not report a parental genotype comparison or a de novo observation, whether or not maternity and paternity were confirmed; therefore PM6 cannot be assessed.

Rule

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

Evidence considered

• The case materials provide no parental testing results, inheritance statement, or proband-specific de novo observation for NM_001128425.2:c.1258C>A.

Still missing

• Proband variant confirmation
• Parental variant testing or an explicit assumed-de-novo observation

Sources

Reasoning

No case-specific family segregation data are provided. The materials do not identify multiple affected relatives, their genotypes, the number of informative meioses, or phenotype concordance, so co-segregation cannot be assessed. A database signal associating the variant with familial adenomatous polyposis 2 is not a report of segregation in multiple affected family members.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• The prefetch file contains only a low-confidence automated PP1 signal based on the phrase 'familial adenomatous polyposis 2'; it provides no relatives, genotypes, meioses, or segregation observations.
• The literature extract for PMID:25820570 reports functional testing of p.L420M but explicitly provides no variant-specific clinical or segregation observation; it therefore does not support PP1.

Still missing

• Pedigree with affected relatives
• Genotypes of affected relatives
• Phenotype confirmation for each relative
• Number of informative meioses and segregation phase

Sources

Reasoning

PP2 requires both a low rate of benign missense variation in the gene and missense variants being a common disease mechanism. The available evidence documents many MUTYH missense variants being evaluated and p.L420M being functionally retained, but it does not provide a validated gene-level benign-missense-rate assessment or an applicable threshold for that requirement. The required two-part PP2 determination is therefore incomplete.

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

• The MUTYH functional study evaluated 47 missense variants, demonstrating that missense variation occurs in the gene, but it does not quantify the gene's benign missense rate or establish the PP2 gene-level requirement.

Still missing

• A validated MUTYH gene-level assessment showing a low rate of benign missense variation is unavailable.
• A governing threshold or comprehensive evidence that missense variants are a common MUTYH disease mechanism is unavailable.

Sources

Reasoning

The available case materials do not provide a patient phenotype or family history for this individual that can be judged highly specific for a single-genetic-etiology disease. The literature packet contains no verified exact-variant phenotype extraction sufficient to establish PP4.

Rule

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

Evidence considered

• The case materials do not state a patient phenotype or family history for this variant.
• The available literature extracts do not provide a verified exact-variant phenotype assessment usable for PP4.

Still missing

• Patient-level phenotype and family-history information is missing.
• No verified exact-variant phenotype report establishes a highly specific disease presentation.

Sources

Reasoning

BS2 cannot be assessed from the available data. The governing rule requires the variant to be observed in a healthy adult individual in the homozygous state for a recessive disorder, with full penetrance expected at an early age. gnomAD reports one homozygote in gnomAD v2.1, one homozygote in the non-cancer v2.1 exomes, and two homozygotes in gnomAD v4.1, but these records do not establish that the individuals were healthy adults, their ages, clinical status, or whether full early-age penetrance is expected for MUTYH-associated polyposis. The population observations therefore do not satisfy the complete BS2 evidence requirement.

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 all-comers reports 1 homozygote; gnomAD v2.1 non-cancer exomes reports 1 homozygote; gnomAD v4.1 all-comers reports 2 homozygotes.
• The governing MUTYH framework identifies autosomal-recessive inheritance but releases no criterion-specific VCEP rules or phenotype/age documentation for these population participants.
• The available gnomAD records provide allele counts and homozygote counts, not verified healthy-adult status, age, clinical phenotype, or penetrance assessment for each homozygote.

Still missing

• No verified age and clinical-health information is available for the gnomAD homozygous individuals.
• No case-specific evidence establishes full penetrance at an early age for the relevant MUTYH-associated disorder.

Sources

Reasoning

No case-specific family data document affected relatives who lack the variant. The available materials contain no pedigree, affected-relative genotypes, phenotype verification, or evaluation of phenocopy and locus heterogeneity; therefore lack of segregation cannot be assessed.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• The case materials provide no affected-relative genotypes or explicit non-segregation observation for NM_001128425.2:c.1258C>A.
• No family-level information is available to evaluate the ACMG/AMP caveat concerning phenocopies or multiple pathogenic variants.

Still missing

• Pedigree identifying affected relatives
• Variant testing in affected relatives
• Phenotype verification and age-related assessment
• Assessment of phenocopy or more than one pathogenic variant

Sources

Reasoning

BP1 requires evidence that primarily truncating variants are known to cause disease. The available MUTYH functional study documents a substantial set of missense variants and reports p.L420M as functionally retained, but it does not establish that disease-causing MUTYH variants are primarily truncating or provide a gene-level variant-spectrum analysis meeting BP1. The criterion cannot be determined from the available evidence.

Rule

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

Evidence considered

• The reviewed functional study evaluated 47 MUTYH missense variants and classified p.L420M as functionally retained, but it does not quantify the proportion of pathogenic truncating versus missense variants.

Still missing

• A validated MUTYH disease variant-spectrum analysis demonstrating primarily truncating pathogenic variants is unavailable.

Sources

Reasoning

BP2 cannot be assessed from the available evidence. No affected-proband or family-level observation documents NM_001128425.2:c.1258C>A in trans with a pathogenic variant in a fully penetrant dominant disorder, and no observation documents it in cis with a pathogenic variant. The available ClinVar aggregate record, functional paper, and population observations do not establish either required phase relationship.

Rule

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

• ClinVar variation 41752 provides aggregate classifications and cited literature but no phase-resolved cis or trans observation for this variant.
• The CSPEC record identifies the relevant MUTYH disorder as autosomal recessive and has no released criterion specifications; this does not supply the phase evidence required for BP2.
• The available functional study of p.L420M and population frequency data do not establish cis or trans phase with a pathogenic allele.

Still missing

• Evidence for a pathogenic variant in cis or trans with c.1258C>A is absent.
• Phase-resolved family or proband data are absent.
• For the trans pathway, a fully penetrant dominant gene/disorder context is not documented.

Sources

Reasoning

No case-level evidence identifies an alternate molecular basis for the disease in an individual carrying NM_001128425.2:c.1258C>A. The available literature and ClinVar materials do not document a qualifying alternate pathogenic variant or other molecular diagnosis in the relevant case.

Rule

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

Evidence considered

• No available case report documents an alternate molecular basis for disease in a carrier of this exact variant.
• ClinVar classifications and general variant observations do not establish BP5 without a documented alternate molecular diagnosis.

Still missing

• Case-level testing results for alternate molecular causes are not provided.

Sources