Submissions for variant NM_000059.4(BRCA2):c.4183G>T (p.Ala1395Ser)

gnomAD frequency: 0.00001  dbSNP: rs431825318

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165596	SCV000216330	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-08	criteria provided, single submitter	clinical testing	The p.A1395S variant (also known as c.4183G>T and 4411G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 4183. The alanine at codon 1395 is replaced by serine, an amino acid with similar properties. This amino acid position is not well 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	RCV000082926	SCV000488378	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000766618	SCV000568000	uncertain significance	not provided	2015-09-20	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4183G>T at the cDNA level, p.Ala1395Ser (A1395S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 4411G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala1395Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala1395Ser occurs at a position that is not conserved and is located within the region of interaction with POLH (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ala1395Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546266	SCV000635347	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1395 of the BRCA2 protein (p.Ala1395Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28651617, 36329109). ClinVar contains an entry for this variant (Variation ID: 96805). 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.
Mendelics	RCV000082926	SCV001139083	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165596	SCV001736201	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1395 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Genetics Program, Instituto Nacional de Cancer	RCV000546266	SCV002515271	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165596	SCV003848748	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330428	SCV004037830	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4183G>T (p.Ala1395Ser) 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 241566 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4183G>T has been reported in the literature in individuals affected with breast or ovarian cancer (e.g., Guindalini_2022, Matta_2022, Buzolin_2017). However, these reports do not 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. The following publications have been ascertained in the context of this evaluation (PMID: 28651617, 35264596, 36329109). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; eight submitters classified the variant as a variant of uncertain significance and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004804084	SCV005424424	uncertain significance	BRCA2-related cancer predisposition	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1395 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766618	SCV005624423	uncertain significance	not provided	2024-08-29	criteria provided, single submitter	clinical testing	The BRCA2 c.4183G>T (p.Ala1395Ser) variant has been reported in the published literature in individuals with a personal and/or family history of BRCA2-related cancers (PMID: 36329109 (2022), 35264596 (2022), 31853058 (2020), 28651617 (2017)), and described 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, 0.000013 (2/152112 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.
Sharing Clinical Reports Project (SCRP)	RCV000082926	SCV000115000	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000478490	SCV000591893	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ala1395Ser variant has not been previously identified in the literature nor by our laboratory. This residue is not conserved in mammals and the variant amino acid (Serine) is present in chicken, decreasing the likelihood this variant has clinical significance. Computational analyses provide inconsistent results (PolyPhen2, AlignGVGD, SIFT), however, this information is not predictive enough to assess the pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance (VUS).