Submissions for variant NM_007294.4(BRCA1):c.4144T>A (p.Cys1382Ser)

gnomAD frequency: 0.00001  dbSNP: rs786202106

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164753	SCV000215427	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-19	criteria provided, single submitter	clinical testing	The p.C1382S variant (also known as c.4144T>A), located in coding exon 10 of the BRCA1 gene, results from a T to A substitution at nucleotide position 4144. The cysteine at codon 1382 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000199782	SCV000254983	benign	Hereditary breast ovarian cancer syndrome	2023-12-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164753	SCV000909277	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-20	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with serine at codon 1382 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000503432	SCV001442747	uncertain significance	not specified	2020-10-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4144T>A (p.Cys1382Ser) 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 248982 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.4144T>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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.
GeneDx	RCV001551019	SCV001771435	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast or ovarian cancer (Li et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4263T>A; This variant is associated with the following publications: (PMID: 15343273, 22737296, 31853058, 29884841, 32377563)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353678	SCV000591496	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Cys1382Ser variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, ClinVar, or BIC databases. The p.Cys1382 residue is not conserved in mammals and the variant amino acid serine (Ser) is present in chicken, African clawed frog, and purple sea urchin, increasing the likelihood that this variant does not have clinical significance. In addition, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and one out of five 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 unknown significance.