Submissions for variant NM_000059.4(BRCA2):c.8299C>T (p.Pro2767Ser)

dbSNP: rs587782619

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132002	SCV000187061	likely benign	Hereditary cancer-predisposing syndrome	2020-02-25	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.
GeneDx	RCV000587651	SCV000570333	uncertain significance	not provided	2016-05-13	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8299C>T at the cDNA level, p.Pro2767Ser (P2767S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 8527C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro2767Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Pro2767Ser occurs at a position that is conserved across species and is located in the SHFM1 binding domain (Marston 1999). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Pro2767Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587651	SCV000695140	uncertain significance	not provided	2015-10-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8299C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Ser. 5/5 in-silico tools predict this variant to be damaging. This variant was not found in 120932 control chromosomes, and it has not been reported in affected individuals via peer reviewed publications (identified in a 28 y/o affected by sporadic breast fibrocystic dysplasia reported in a dissertation) nor evaluated for functional impact by in vivo/vitro studies. One reputable diagnostic lab classifies the variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000132002	SCV001355821	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 2767 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not impact homology-directed DNA repair activity (PMID: 35736817). This variant has been reported in three individuals affected with breast or ovarian cancer (PMID: 32438681, 32854451) and in two unaffected individuals (PMID: 30287823, 31214711, 32980694). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001237414	SCV001410173	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2767 of the BRCA2 protein (p.Pro2767Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 31569370, 32438681, 32854451, 34178674). ClinVar contains an entry for this variant (Variation ID: 142656). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 31569370). 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.
All of Us Research Program, National Institutes of Health	RCV003998126	SCV004845632	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 2767 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not impact homology-directed DNA repair activity (PMID: 35736817). This variant has been reported in three individuals affected with breast or ovarian cancer (PMID: 32438681, 32854451) and in two unaffected individuals (PMID: 30287823, 31214711, 32980694). This variant has not been identified 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.