Submissions for variant NM_000059.4(BRCA2):c.2125C>G (p.Leu709Val)

dbSNP: rs80358489

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164754	SCV000215428	likely benign	Hereditary cancer-predisposing syndrome	2018-02-28	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	RCV000236275	SCV000293480	likely benign	not provided	2020-08-17	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31131967, 10923033, 23718828, 16758124, 15937982)
Color Diagnostics, LLC DBA Color Health	RCV000164754	SCV000688744	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 709 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 an individual with a personal or family history of breast and/or ovarian cancer (PMID: 16758124). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 2/53461 controls (PMID: 33471991 ; Leiden Open Variation Database DB-ID BRCA2_005967). This variant has been identified in 3/250930 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001297703	SCV001486732	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 709 of the BRCA2 protein (p.Leu709Val). This variant is present in population databases (rs80358489, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15937982, 16758124). ClinVar contains an entry for this variant (Variation ID: 51247). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164754	SCV003846513	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).
PreventionGenetics, part of Exact Sciences	RCV004537189	SCV004105269	uncertain significance	BRCA2-related disorder	2023-04-24	criteria provided, single submitter	clinical testing	The BRCA2 c.2125C>G variant is predicted to result in the amino acid substitution p.Leu709Val. This variant was previously reported in a large breast cancer cohort (Infante et al. 2006. PubMed ID: 16758124, reported as c.2353C>G/L709V). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32910617-C-G). In the ClinVar database, this variant has conflicting interpretations of 'likely benign' and 'uncertain' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/51247/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004803147	SCV004847009	uncertain significance	BRCA2-related cancer predisposition	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 709 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 an individual with a personal or family history of breast and/or ovarian cancer (PMID: 16758124). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 2/53461 controls (PMID: 33471991 ; Leiden Open Variation Database DB-ID BRCA2_005967). This variant has been identified in 3/250930 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237466	SCV005886540	uncertain significance	not specified	2025-02-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2125C>G (p.Leu709Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. In addition, a report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). The variant allele was found at a frequency of 1.2e-05 in 250930 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2125C>G has been reported in the literature in individuals affected with a personal and/or family history of breast/ovarian cancer (e.g. Velasco_2005, Infante_2006, Dorling_2021), but was also found in controls (e.g. Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16758124, 33471991, 31112341, 31294896, 15937982). ClinVar contains an entry for this variant (Variation ID: 51247). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113018	SCV000146009	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000236275	SCV001957356	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000236275	SCV001973012	likely benign	not provided		no assertion criteria provided	clinical testing