Submissions for variant NM_000059.4(BRCA2):c.6148G>A (p.Val2050Ile)

dbSNP: rs80358854

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240684	SCV000265935	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Ambry Genetics	RCV000510133	SCV000607851	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-18	criteria provided, single submitter	clinical testing	The p.V2050I variant (also known as c.6148G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6148. The valine at codon 2050 is replaced by isoleucine, an amino acid with highly similar properties. In one study, this alteration was detected in 1/645 women with breast cancer from China, and was absent from women with benign breast disease (n=342) and controls (n=319) (Suter NM, Cancer Epidemiol. Biomarkers Prev. 2004 Feb; 13(2):181-9). This alteration was also identified in the germline of 1/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS One, 2016 Jun;11:e0156789). This alteration has also been reported with a carrier frequency of 0/7051 unselected breast cancer patients and 3/11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000763893	SCV000894828	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000510133	SCV000906924	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2050 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 two individuals affected with breast cancer (PMID: 14973102, 27257965) and in breast, prostate and pancreatic cancer case-control studies in which this variant was only detected in unaffected individuals and absent in cancer cases (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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194410	SCV001363945	uncertain significance	not specified	2021-10-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6148G>A (p.Val2050Ile) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 298992 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6148G>A has been reported in the literature in two Chinese individuals affected with breast cancer (Suter_2004, Zhong_2016). The variant was also reported in a large case-control association study, involving unselected breast cancer (BrC) patients and controls of Japanese ancestry, and was found in 5 healthy (3/11241 female, 2/12490 male) controls and in none of the affected cases (7051 female and 53 male) (Momozawa_2018). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.4485-2A>G), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852947	SCV002142913	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2050 of the BRCA2 protein (p.Val2050Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10923033, 14973102, 27257965, 30702160, 35918668). ClinVar contains an entry for this variant (Variation ID: 52019). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 37731132). 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.
GeneDx	RCV003156222	SCV003845782	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Identified in patients with breast cancer, but also in cancer-free controls (Suter et al., 2004; Zhong et al., 2016; Momozawa et al., 2018; Chen et al., 2020; Dong et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6376G>A; This variant is associated with the following publications: (PMID: 30287823, Yongzhe2018[CaseReport], 30702160, Dong2015[CaseReport], 27257965, 14973102, 31825140, 29884841, 35300142, 32377563, 32091409, 32467295)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510133	SCV003850975	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).
All of Us Research Program, National Institutes of Health	RCV004803869	SCV005424522	uncertain significance	BRCA2-related cancer predisposition	2024-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2050 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 two individuals affected with breast cancer (PMID: 14973102, 27257965) and in breast, prostate and pancreatic cancer case-control studies in which this variant was only detected in unaffected individuals and absent in cancer cases (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.
Sharing Clinical Reports Project (SCRP)	RCV000083123	SCV000115197	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083123	SCV000146779	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354612	SCV001549266	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val2050Ile variant was identified in 3 of 16606 proband chromosomes (frequency: 0.00018) from individuals or families with breast cancer and was present in 3 of 23120 control chromosomes (frequency: 0.00013) from healthy individuals (Suter 2004, Momozawa 2018, Zhong 2016,Dong 2015). The variant was also identified in dbSNP (ID: rs80358854) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Sharing Clinical Reports, BIC, and West China Hospital), and in the LOVD 3.0 database.The variant was not identified in the UMD-LSDB database. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Val2050 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; however this information is not predictive enough to assume pathogenicity. 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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250519	SCV002520817	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only