Submissions for variant NM_000059.4(BRCA2):c.6988A>G (p.Ile2330Val)

dbSNP: rs876661032

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585970	SCV000279278	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or prostate cancer (Fernandes et al., 2016; Paulo et al., 2018; Ren et al., 2021; Guindalini et al., 2022; Matta et al., 2022); Also known as 7216A>G; This variant is associated with the following publications: (PMID: 29161300, 28651617, 27741520, 29659569, 33007869, 29884841, 32377563, 36977404, 36329109, 34196900, 35264596)
Invitae	RCV000477387	SCV000549819	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-10	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 2330 of the BRCA2 protein (p.Ile2330Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer and/or ovarian cancer (PMID: 27741520, 28651617, 29161300, 36329109). ClinVar contains an entry for this variant (Variation ID: 234463). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260262	SCV000695019	uncertain significance	not specified	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6988A>G (p.Ile2330Val) 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 was absent in 249986 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6988A>G has been reported in the literature in an HBOC proband with a personal history of breast cancer at age 24 and a family history of breast cancer with no reported co-segregation (Fernandes_2016), as a VUS in another study reporting HBOC probands from Southern Brazil (Alemar_2017), as a VUS specimen previously analyzed at another clinical laboratory (Buzolin_2017), in a study of cancer predisposition panel sequencing in patients with prostate cancer (Paulo_2018). None of these report(s) 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. Six 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 uncertain significance.
Mendelics	RCV000477387	SCV000838847	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585970	SCV000889119	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 36329109 (2022), 28651617 (2017) and 27741520 (2016)) and prostate cancer (PMID: 29659569 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.
Color Diagnostics, LLC DBA Color Health	RCV000776229	SCV000911444	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-25	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2330 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 individuals with a personal or family history of breast and/or ovarian cancer or prostate cancer (PMID: 27741520, 29161300, 29659569, 33471991; Leiden Open Variation Database DB-ID BRCA2_001102, 35264596, 35980532, 36329109, 36977404). 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.
Mendelics	RCV000989057	SCV001139165	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000477387	SCV002515137	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Ambry Genetics	RCV000776229	SCV002665327	likely benign	Hereditary cancer-predisposing syndrome	2020-12-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355885	SCV001550899	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ile2330Val variant was identified in 2 of 1534 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alemar 2017, Fernandes 2016). The variant was also identified in dbSNP (ID: rs876661032) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, and Integrated Genetics/Laboratory Corporation of America), and LOVD 3.0 (2x). The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, or Zhejiang University databases. It was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ile2330 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. 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.