ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3227T>C (p.Val1076Ala)

gnomAD frequency: 0.00001  dbSNP: rs1060502498
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000477400 SCV000549882 uncertain significance Hereditary breast ovarian cancer syndrome 2022-08-14 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 409609). This missense change has been observed in individual(s) with breast cancer (PMID: 21318380). This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1076 of the BRCA2 protein (p.Val1076Ala).
Ambry Genetics RCV000564131 SCV000664820 likely benign Hereditary cancer-predisposing syndrome 2022-04-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985497 SCV001133749 uncertain significance not provided 2019-07-26 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000564131 SCV001735710 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-27 criteria provided, single submitter clinical testing This missense variant replaces valine with alanine at codon 1076 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 21318380). This variant has been identified in 3/239916 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000564131 SCV003851785 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
GeneDx RCV000985497 SCV005332990 uncertain significance not provided 2023-11-21 criteria provided, single submitter clinical testing Observed in individuals with a personal and family history of BRCA2-related cancers (PMID: 21318380); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3455T>C; This variant is associated with the following publications: (PMID: 31131967, 29884841, 32377563, 21318380)
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355655 SCV001550599 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Val1076Ala variant was identified in 2 of 2662 proband chromosomes (frequency: 0.0007) from individuals or families with breast cancer and was not identified in 360 control chromosomes from healthy individuals (Hansen 2011). The variant was also identified in dbSNP (ID: rs1060502498) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae and Ambry Genetics), and in UMD-LSDB (1x as unclassified variant). The variant was not identified in the COGR, Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, or Zhejiang University database. The variant was identified in control databases in 3 of 235040 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 3 of 16788 chromosomes (freq: 0.000179), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Val1076 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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