Submissions for variant NM_000059.4(BRCA2):c.7331A>T (p.Asp2444Val)

dbSNP: rs431825352

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129097	SCV000183808	likely benign	Hereditary cancer-predisposing syndrome	2022-03-29	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471031	SCV000549683	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129097	SCV000683866	likely benign	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001296	SCV001158476	uncertain significance	not specified	2019-05-13	criteria provided, single submitter	clinical testing	The BRCA2 c.7331A>T; p.Asp2444Val variant (rs431825352) is reported in the literature in at least one individual in a breast and/or ovarian cancer cohort (Singh 2018). This variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 140873), and is found in the South Asian population with an allele frequency of 0.072% (22/30460 alleles) in the Genome Aggregation Database. The aspartic acid at codon 2444 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Asp2444Val variant is uncertain at this time. References: Singh J et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat. 2018 Jul;170(1):189-196.
GeneDx	RCV001576378	SCV001803551	uncertain significance	not provided	2025-02-14	criteria provided, single submitter	clinical testing	Observed in individuals with history of breast and/or ovarian cancer (PMID: 29470806); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 7559A>T; This variant is associated with the following publications: (PMID: 31422574, 32377563, 29884841, 31853058, 29470806)
Sema4, Sema4	RCV000129097	SCV002531851	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV001576378	SCV003830144	uncertain significance	not provided	2021-02-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001001296	SCV004027471	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997479	SCV004844396	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001576378	SCV005625277	uncertain significance	not provided	2024-01-02	criteria provided, single submitter	clinical testing	The BRCA2 c.7331A>T (p.Asp2444Val) variant has been reported in the published literature in a cohort of individuals with breast and/or ovarian cancer (PMID: 29470806 (2018), 32885271 (2021)). This variant has also been identified in a reportedly healthy individual (PMID: 31422574 (2019)). The frequency of this variant in the general population, 0.00072 (22/30460 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357165	SCV001552538	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp2444Val variant was not identified in the literature nor was it identified in the MutDB, LOVD 3.0, UMD-LSDB, BIC, ARUP Laboratories, Cosmic, and Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs431825352) as “Uncertain Significance allele” and in the ClinVar and Clinvitae databases as uncertain significance by Ambry Genetics and Invitae. The variant was also identified in control databases in 22 of 245620 chromosomes at a frequency of 0.00009 in the following populations: South Asian in 21 of 30616 chromosomes (freq. 0.0007) and Other in 1 of 5476 chromosomes (freq. 0.0002), but was not seen in African, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, and European Finnish populations increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017)". The p.Asp2444 residue is not conserved in mammals and the variant amino acid (Val) is present in Rattus norvegicus, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; increasing the likelihood that this variant does not have clinical significance: 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 2 susceptibility protein functional domains increasing the likelihood that it may have clinical significance. 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.