Submissions for variant NM_000059.4(BRCA2):c.4957A>G (p.Thr1653Ala)

dbSNP: rs587782186

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130816	SCV000185712	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-26	criteria provided, single submitter	clinical testing	The p.T1653A variant (also known as c.4957A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4957. The threonine at codon 1653 is replaced by alanine, 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000210984	SCV000267774	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000496784	SCV000588095	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Invitae	RCV000637549	SCV000759013	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130816	SCV000906095	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1653 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. In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR= 1.768 (95%CI 0.16 to 19.503); p-value=1; Leiden Open Variation Database DB-ID BRCA2_002507) (PMID: 33471991). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496784	SCV001363362	uncertain significance	not specified	2019-12-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4957A>G (p.Thr1653Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 241228 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4957A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283929	SCV001469437	uncertain significance	not provided	2021-05-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001283929	SCV002765530	uncertain significance	not provided	2022-12-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5185A>G; This variant is associated with the following publications: (PMID: 26941049, 31911673, 31853058, 32377563, 29884841)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130816	SCV003852237	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354039	SCV000591933	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Thr1653Ala variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, or BIC databases. It was identified in ClinVar database (1x by Ambry with uncertain significance) and UMD (1X as a class 3-UV variant). The p.Thr1653 residue is not conserved in mammals and the variant amino acid Alanine was observed in chicken increasing the likelihood this variant may not have clinical significance. Computational analyses (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 c.4957A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 4 of 5 different programs. 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	RCV000210984	SCV004243645	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing