Submissions for variant NM_000059.4(BRCA2):c.4819A>G (p.Ile1607Val)

gnomAD frequency: 0.00002  dbSNP: rs200582465

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221891	SCV000273354	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-29	criteria provided, single submitter	clinical testing	The p.I1607V variant (also known as c.4819A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4819. The isoleucine at codon 1607 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in one study examining the frequency of BRCA1 and BRCA2 mutations among the Chinese population; the p.I1607V variant was identified in 1/319 healthy controls and was not identified in 645 women with breast cancer or in 342 women with benign breast disease (Suter NM et al. Cancer Epidemiol. Biomarkers Prev. 2004 Feb;13:181-9). This alteration was also identified in an individual diagnosed with ovarian cancer (Luo Y et al. Int J Gen Med, 2022 Mar;15:2773-2786). 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.
GeneDx	RCV000657070	SCV000279511	uncertain significance	not provided	2024-12-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 5047A>G; This variant is associated with the following publications: (PMID: 31825140, 32467295, 27157322, 33471991, 14973102, 35300142)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233915	SCV000283250	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1607 of the BRCA2 protein (p.Ile1607Val). This variant is present in population databases (rs200582465, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 31825140, 35300142). ClinVar contains an entry for this variant (Variation ID: 37926). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657070	SCV000600612	uncertain significance	not provided	2023-11-08	criteria provided, single submitter	clinical testing	The BRCA2 c.4819A>G (p.Ile1607Val) variant has been reported in the published literature in individuals with ovarian cancer (PMID: 35300142 (2022)), esophageal squamous cell carcinoma (PMID: 31396961 (2020)) as well as in unaffected individuals (PMID: 14973102 (2004), 27157322 (2016)). In a large-scale breast cancer association study, the variant was observed in breast cancer cases and in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). This variant has been reported to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.00016 (3/18380 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Counsyl	RCV000031507	SCV000786415	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-05-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221891	SCV000903839	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1607 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 affected with ovarian cancer (PMID: 35300142). In a breast cancer case-control meta-analysis this variant was reported in 4/60462 cases and 2/53459 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002498). This variant has been identified in 4/250110 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	RCV000221701	SCV001361964	uncertain significance	not specified	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4819A>G (p.Ile1607Val) 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. The variant allele was found at a frequency of 2e-05 in 250748 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4819A>G has been reported in the literature in individuals affected with breast, ovarian or endometrial cancer, as well as unaffected controls (e.g. Suter_2004, Dorling_2021, Luo_2022, Darabi_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant was reported in one of these cases (BRCA2 c.2589delinsAA, p.N863K), providing supporting evidence for a benign role. 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: 14973102, 27157322, 35300142, 36557020, 33471991). ClinVar contains an entry for this variant (Variation ID: 37926). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000221891	SCV003852120	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).
Sharing Clinical Reports Project (SCRP)	RCV000031507	SCV000054112	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657070	SCV000591928	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Ile1607Val variant was identified by Suter (2004) in a healthy control subject, but was not identified in any of the breast cancer affected probands from this study. The variant was listed in the UMD as an unclassified variant in one sample. It was identified in dbSNP (ID: rs200582465) “With allele of Uncertain significance”, with a minor allele frequency of 0.0005 (1000 Genomes Project); however, this is based on only one observation of the variant allele. The variant was not listed in any of the other databases searched, including HGMD, COSMIC, LOVD and BIC. This residue is not conserved in mammals or lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out 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 unknown significance.
BRCAlab, Lund University	RCV000031507	SCV004243640	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing