The HOXB13 NM_006361.6:c.251G>A (NP_006352.2:p.(Gly84Glu)) missense variant has previously been reported in somatic cancers (COSMIC; COSV51706067, n = 2 times). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.HOXB13 encodes a homeobox transcription factor that helps regulate embryonic body patterning, cellular differentiation, proliferation, and prostate cell identity. It is associated with familial and inherited risk of prostate cancer, and its activity can either promote or suppress tumor growth depending on the cellular context. HOXB13 is also involved in several other cancers, where it may be overactive or reduced, including prostate, breast, colorectal, and kidney cancers.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting strength: complete co-segregation was reported in 34 families, with over-transmission to affected sons at P=6.5×10−6.
No benign criterion marked as applied in the recorded assessment.
VUS: PP1 at supporting strength is the only applied criterion and does not satisfy any generic ACMG/AMP pathogenic or benign combination threshold.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 2,798 / 1,613,966 alleles. Recorded AF 0.00173362. Recorded homozygote count 5.
This variant is present in gnomAD v2.1 (AF= 0.00188006; MAF= 0.18801%, 528/280842 alleles, homozygotes = 2) and has highest observed frequency in the European (Finnish) population (AF= 0.00761806; MAF= 0.76181%, 191/25072 alleles, homozygotes = 1); grpmax FAF= 0.00217612.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0011952624144300772, 22/18406 alleles, homozygotes = 0).
Recorded REVEL score: 0.448. Refer to the recorded PP3/BP4 rationale for interpretation.
16 Pathogenic · 12 Likely pathogenic · 1 Uncertain significance · 1 Likely Pathogenic · 1 pathogenic · 1 association. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV51706067, n = 2 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 9 not met · 13 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Segregation evidence supports PP1 at supporting strength; PS2 and PM6 lack proband-level de novo documentation, and BS4 lacks documented affected non-carriers.
Generic ACMG/AMP rules govern because no HOXB13 VCEP or gene-specific criteria specification is present.
PS4 is not met from the verified evidence available here.
PP4 and BP5 are not assessed because the case lacks the phenotype/family-history specificity and alternate-molecular-basis information required by their definitions.
PP5 and BP6 are not met because the exact-variant ClinVar record has zero expert-panel submissions.
Population evidence does not support BA1, BS1, or PM2. BS2 cannot be applied because aggregate gnomAD homozygote counts do not document healthy-adult status and the associated HOXB13 prostate-cancer phenotype is late-onset and incompletely penetrant.
No criteria match.
The HOXB13 c.251G>A (p.G84E) variant was studied in 112 European-descent prostate-cancer families. The report describes complete co-segregation in 34 families, mixed co-segregation overall, and significant over-transmission to affected sons (P=6.5×10−6). These findings support co-segregation with prostate cancer in multiple affected family members, although incomplete penetrance and genetic heterogeneity warrant human review of the strength.
PP1: Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data.
The governing ACMG/AMP PS4 threshold is OR >5.0 with a 95% confidence interval that excludes 1.0. The selectively read, source-registry-backed exact-variant studies report OR 4.42 (95% CI 2.56-7.64; PMID:23064873), OR 4.51 (95% CI 3.28-6.20; PMID:24026887), OR 3.4-3.5 (PMID:22841674), and OR 3.248 (95% CI 2.313-4.560; PMID:26517352). The required comparisons are 4.42 > 5.0? no, 4.51 > 5.0? no, 3.4 > 5.0? no, and 3.248 > 5.0? no. Although the literature_pass classifier listed an additional familial case-control lead with a reported OR of 7.9, that PMID has no source_registry entry or paper_extracts finding in this case, so it is not used as auditable evidence. PS4 is not met from the verified evidence available here.
Note 1: 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.
PM2 is not met. The variant is observed in the relevant control population datasets: gnomAD v2.1 non-cancer exomes AF 0.0018616 (438/235282 alleles), gnomAD v3.1 non-cancer genomes AF 0.00146721 (217/147900), and gnomAD v4.1 all-comers AF 0.00173362 (2798/1613966), with homozygotes reported in each dataset. These frequencies are not absent or extremely low for this dominant cancer-susceptibility context.
PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a missense substitution, NP_006352.2:p.(Gly84Glu), so the applicable generic computational path is REVEL only; SpliceAI, BayesDel, and other predictors are not counted. REVEL is 0.448, which is below the generic PP3 supporting threshold of >= 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. The score is also in the gray zone and cannot be replaced by the available SpliceAI score.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The governing PP5 rule concerns a reputable source reporting the variant as pathogenic when the evidence is unavailable for independent evaluation. Under the specified generic rule, PP5 may be applied only for an exact-variant ClinVar expert-panel classification. ClinVar variation 128031 has no expert-panel submissions; it has laboratory submissions and an aggregate Pathogenic/Likely pathogenic record. Therefore PP5 is not met and those non-expert classifications are not used to trigger it.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The variant is present in gnomAD v2.1 non-cancer exomes at AF 0.0018616 (438/235282 alleles), gnomAD v3.1 non-cancer genomes at AF 0.00146721 (217/147900), and gnomAD v4.1 all-comers at AF 0.00173362 (2798/1613966). The highest reported ancestry-specific frequency is 0.00769038 in Finnish individuals in gnomAD v4.1, well below the generic stand-alone threshold of 0.05 (5%).
BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met on the available population data. The highest observed ancestry-specific frequency is 0.00769038 (0.769%) in Finnish individuals; the gnomAD v4.1 all-comers group maximum is 0.00178665 and the gnomAD v3.1 non-cancer group maximum is 0.00171266, all below the supplied generic 0.01 default. The variant is a known Finnish founder allele associated with prostate-cancer susceptibility, and the available study estimated cumulative carrier prostate-cancer risk to age 80 at 33%, indicating reduced, late-onset penetrance; therefore the default 1% threshold does not independently support BS1.
BS1: Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BP1 applies when a gene's disease mechanism is primarily truncating variation. The available HOXB13 evidence instead documents a recurrent missense disease allele, p.Gly84Glu, with increased prostate-cancer risk in population-based and familial studies (odds ratios 3.4–3.5 and 4.42). This does not support a primarily truncating disease mechanism for this missense interpretation.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense substitution, NP_006352.2:p.(Gly84Glu), so the applicable generic computational path is REVEL only; SpliceAI, BayesDel, and other predictors are not counted. REVEL is 0.448, which is above the generic BP4 supporting threshold of <= 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so BP4 is not met. The gray-zone REVEL result does not permit substituting the low SpliceAI score as BP4 evidence.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The governing BP6 rule concerns a reputable source reporting the variant as benign when the evidence is unavailable for independent evaluation. Under the specified generic rule, BP6 may be applied only for an exact-variant ClinVar expert-panel classification. ClinVar variation 128031 has no expert-panel submissions and does not provide an expert-panel benign or likely-benign classification. Therefore BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is HOXB13 p.Gly84Glu (NM_006361.6:c.251G>A). The available evidence documents this exact missense change but does not identify a previously established pathogenic HOXB13 variant caused by a different nucleotide change that produces the same Gly84Glu amino-acid substitution. Therefore the same-amino-acid requirement cannot be verified.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No case-level observation documents this variant as de novo in an affected proband. The available evidence does not provide confirmed maternity and paternity, and it does not establish absence of a family history.
PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No variant-specific in vitro or in vivo functional study was identified for HOXB13 c.251G>A (p.Gly84Glu). The reviewed literature consists of genetic association and segregation studies, including family genotyping and epidemiologic meta-analyses, not assays measuring the variant's effect on HOXB13 function. PMID:15964834 provides functional data for wild-type HOXB13 overexpression in rat epidermal keratinocytes but does not mention or test p.Gly84Glu, so it cannot establish a damaging effect for this variant. OncoKB labels the variant's biological effect as loss-of-function, but that curated annotation is not itself a validated functional assay and is insufficient to apply PS3.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
HOXB13 has no governing VCEP specification or authoritative domain table in this case. A meta-analysis states that G84E lies within the first MEIS-interacting domain, but the available evidence does not establish that region as a qualifying critical and well-established functional domain without benign variation; the hotspot source reports no statistically significant hotspot. The generic PM1 threshold therefore cannot be confirmed.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The evaluated variant is p.Gly84Glu. No different missense substitution at HOXB13 residue 84 with established pathogenic evidence was identified in the available comparator evidence. The exact p.Gly84Glu variant itself cannot serve as the required different missense comparator, so PM5 cannot be assessed as met.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No case-level observation documents this variant as assumed de novo in an affected proband. The available evidence does not provide an unconfirmed parental-origin assessment that would support PM6.
PM6: Assumed de novo, but without confirmation of paternity and maternity.
HOXB13 missense disease mechanism is supported by recurrent G84E association in prostate-cancer cohorts, including odds ratios of 3.4–3.5 and 4.42. However, the available evidence does not establish that HOXB13 has a low rate of benign missense variation at the gene level. Because both elements of PP2 are required, PP2 is not assessed.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing PP4 rule requires a patient's phenotype or family history highly specific for a disease with a single genetic etiology. The case materials identify the HOXB13 variant but do not provide the patient's phenotype, detailed family history, or evidence that the phenotype is highly specific for a single genetic etiology. The criterion therefore cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD reports homozygotes (2 in gnomAD v2.1 non-cancer exomes, 1 in gnomAD v3.1 non-cancer genomes, and 5 in gnomAD v4.1 all-comers), but these records do not document that any homozygous individual was a healthy adult. More importantly, the relevant HOXB13 phenotype is prostate-cancer susceptibility with late onset and incomplete penetrance, rather than a disorder for which full penetrance is expected at an early age. The available population study estimated only 33% cumulative prostate-cancer risk to age 80 for carriers, so a population homozygote count alone cannot satisfy BS2.
BS2: 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.
No variant-specific in vitro or in vivo functional study was identified that demonstrates no damaging effect of HOXB13 c.251G>A (p.Gly84Glu) on protein function or splicing. The reviewed variant-level studies were genetic association, segregation, or epidemiologic analyses, while PMID:15964834 examined wild-type HOXB13 overexpression and did not test p.Gly84Glu. Therefore, the available evidence cannot establish benign functional evidence for BS3, at any strength.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available family study reports mixed co-segregation and genetic heterogeneity but does not identify specific affected family members who lack the variant. Without documented affected non-carriers in a family, lack of segregation cannot be established.
BS4: Lack of segregation in affected members of a family.
BP2 requires observation with a pathogenic variant either in trans for a fully penetrant dominant gene/disorder or in cis for any inheritance pattern. The available evidence reports HOXB13 G84E in affected prostate-cancer families and transmission to affected offspring, but does not identify a second pathogenic variant in the same individuals or establish cis/trans phase; the criterion therefore cannot be assessed.
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.
The governing BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The available case evidence does not document an alternate pathogenic molecular cause in the same case, and no BP5-specific quantitative rule is supplied. The criterion is therefore not assessed.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_006361.6:c.251G>A in HOXB13 is a missense substitution predicted to produce NP_006352.2:p.(Gly84Glu). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for HOXB13, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is restricted to recessive disorders and requires the assessed variant to be detected in trans with a pathogenic variant, with phase established through parental or offspring testing. The available HOXB13 evidence concerns a dominant prostate-cancer susceptibility phenotype in affected men and familial transmission, not a recessive disorder or a biallelic disease mechanism; therefore PM3 is not applicable.
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_006361.6:c.251G>A in HOXB13 is a missense substitution predicted to produce NP_006352.2:p.(Gly84Glu). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for HOXB13, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_006361.6:c.251G>A in HOXB13 is a missense substitution predicted to produce NP_006352.2:p.(Gly84Glu). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for HOXB13, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006361.6:c.251G>A in HOXB13 is a missense substitution predicted to produce NP_006352.2:p.(Gly84Glu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for HOXB13, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in HOXB13, mapped onto the exon structure of NM_006361.6. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (Finnish)491 / 63,846 | 0.00772 hom |
| European (non-Finnish)2185 / 1,180,006 | 0.00192 hom |
| Remaining individuals91 / 62,512 | 0.00151 hom |
| African/African American25 / 75,034 | 0.00033 |
| Admixed American5 / 60,028 | 8.3e-05 |
| Ashkenazi Jewish1 / 29,604 | 3.4e-05 |
| European (Finnish)191 / 25,072 | 0.00761 hom |
| European (non-Finnish)311 / 128,106 | 0.00241 hom |
| Remaining individuals15 / 7,182 | 0.0021 |
| African/African American9 / 24,234 | 0.00037 |
| Ashkenazi Jewish1 / 10,310 | 9.7e-05 |
| Admixed American1 / 35,418 | 2.8e-05 |
This variant is present in gnomAD v4.1 (AF= 0.00173362; MAF= 0.17336%, 2798/1613966 alleles, homozygotes = 5) and has highest observed frequency in the European (Finnish) population (AF= 0.00769038; MAF= 0.76904%, 491/63846 alleles, homozygotes = 2); grpmax FAF= 0.00178665.
This variant is present in gnomAD v2.1 (AF= 0.00188006; MAF= 0.18801%, 528/280842 alleles, homozygotes = 2) and has highest observed frequency in the European (Finnish) population (AF= 0.00761806; MAF= 0.76181%, 191/25072 alleles, homozygotes = 1); grpmax FAF= 0.00217612.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0011952624144300772, 22/18406 alleles, homozygotes = 0).
The variant is a missense substitution, NP_006352.2:p.(Gly84Glu), so the applicable generic computational path is REVEL only; SpliceAI, BayesDel, and other predictors are not counted. REVEL is 0.448, which is below the generic PP3 supporting threshold of >= 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. The score is also in the gray zone and cannot be replaced by the available SpliceAI score.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, NP_006352.2:p.(Gly84Glu), so the applicable generic computational path is REVEL only; SpliceAI, BayesDel, and other predictors are not counted. REVEL is 0.448, which is above the generic BP4 supporting threshold of <= 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so BP4 is not met. The gray-zone REVEL result does not permit substituting the low SpliceAI score as BP4 evidence.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006361.6:c.251G>A in HOXB13 is a missense substitution predicted to produce NP_006352.2:p.(Gly84Glu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for HOXB13, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.448. BayesDel score = 0.187019.
7 paper records listed. 1 cited in the classification.
The G84E mutation was found in 283 subjects from 112 families of European descent, including 194 men with prostate cancer.
Location Results, paragraph 2; Table 1
Context HOXB13 variant genotyping in 2,443 hereditary prostate-cancer families from the International Consortium for Prostate Cancer Genetics; MassARRAY iPLEX genotyping, family-based association testing, and haplotype analysis.
The G84E mutation was associated with a PCa relative risk of 3.4 (95% CI, 2.2–5.4; p = 6.4e−10) in CAPS and 3.5 (95% CI, 2.4–5.2, p = 2.0e−11) in Stockholm-1.
Results, paragraph 2; Table 2; Results, paragraph 5
Men with the HOXB13 G84E variant had a 4.51-fold higher relative risk of PCa compared with non-carriers (95 % CI 3.28–6.20).
Abstract; Results, Meta-analysis results; Discussion
The results presented that HOXB13 p.Gly84Glu mutation contributed to the susceptibility of prostate cancer (OR = 3.248, 95% CI = 2.313–4.560, P < 0.001; Figure 3).
Results, Quantitative data analyses; Table 2; Discussion, first paragraph
Together, these data support a role for Hoxb13 in suppressing proliferation, promoting apoptosis, and driving epidermal differentiation, and they strengthen the possibility that Hoxb13 is involved in wound repair and in the pathogenesis of certain skin diseases.
Abstract; Results and Discussion sections describing HOXB13 overexpression in REK lift cultures
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00173362; MAF= 0.17336%, 2798/1613966 alleles, homozygotes = 5) and has highest observed frequency in the European (Finnish) population (AF= 0.00769038; MAF= 0.76904%, 491/63846 alleles, homozygotes = 2); grpmax FAF= 0.00178665.
This variant is present in gnomAD v2.1 (AF= 0.00188006; MAF= 0.18801%, 528/280842 alleles, homozygotes = 2) and has highest observed frequency in the European (Finnish) population (AF= 0.00761806; MAF= 0.76181%, 191/25072 alleles, homozygotes = 1); grpmax FAF= 0.00217612.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0011952624144300772, 22/18406 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Pathogenic (16 clinical laboratories) and as Likely pathogenic (12 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as association (1 clinical laboratory). (ClinVarID = 128031)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.448. BayesDel score = 0.187019.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51706067, n = 2 times).
This variant does not lie in a statistically significant hotspot.