ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4183G>T (p.Ala1395Ser) (rs431825318)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165596 SCV000216330 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000082926 SCV000488378 uncertain significance Breast-ovarian cancer, familial 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000478490 SCV000591893 uncertain significance not specified 2012-03-30 criteria provided, single submitter clinical testing
Invitae RCV000546266 SCV000635347 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1395 of the BRCA2 protein (p.Ala1395Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 28651617). ClinVar contains an entry for this variant (Variation ID: 96805). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Mendelics RCV000546266 SCV000838795 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000082926 SCV001139083 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082926 SCV000115000 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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