Submissions for variant NM_000059.4(BRCA2):c.3497T>A (p.Val1166Asp)

dbSNP: rs762886975

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166339	SCV000217125	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing	The p.V1166D variant (also known as c.3497T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 3497. The valine at codon 1166 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Illumina Laboratory Services, Illumina	RCV000309640	SCV000383681	uncertain significance	Fanconi anemia complementation group D1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001094081	SCV000383682	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000366646	SCV000816533	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1166 of the BRCA2 protein (p.Val1166Asp). This variant is present in population databases (rs762886975, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186700). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166339	SCV003846652	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).
Myriad Genetics, Inc.	RCV001094081	SCV005084446	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-06-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004692777	SCV005196381	likely benign	Inherited breast cancer and ovarian cancer	2024-05-08	criteria provided, single submitter	clinical testing	BP1,BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356826	SCV001552095	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val1166Asp variant was not identified in the literature nor was it identified in the LOVD 3.0, or UMD-LSDB, databases. The variant was identified in dbSNP (ID: rs762886975) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was identified in control databases in 1 of 245596 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111150 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Val1166 residue is not conserved in mammals and four out of five 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.