ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1441A>G (p.Ile481Val) (rs760559435)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205133 SCV000259458 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 481 of the BRCA2 protein (p.Ile481Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs760559435, ExAC 0.009%). This variant has been observed in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 27062684). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000566955 SCV000665957 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-18 criteria provided, single submitter clinical testing The p.I481V variant (also known as c.1441A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1441. The isoleucine at codon 481 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was identified in 2/2351 Italian breast and/or ovarian cancer patients (Santonocito C et al. Cancers (Basel), 2020 May;12:). 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.
Counsyl RCV000663047 SCV000786092 uncertain significance Breast-ovarian cancer, familial 2 2018-02-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759574 SCV000888978 uncertain significance not provided 2020-03-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000566955 SCV000903457 likely benign Hereditary cancer-predisposing syndrome 2017-05-23 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000663047 SCV001428536 uncertain significance Breast-ovarian cancer, familial 2 2018-05-11 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358420 SCV001554146 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ile481Val variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs760559435) as “With Uncertain significance”, in ClinVar (1x, as uncertain significance, by Invitae), Clinvitae (1x, as uncertain significance), LOVD 3.0 (2x), UMD-LSDB (1x record, as 3-UV), databases. The variant was also identified in control databases in 1 of 239798 chromosomes at a frequency of 0.000004 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.Ile481 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the Breast cancer type 2 susceptibility protein functional domain(s) 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.

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