Submissions for variant NM_000059.4(BRCA2):c.3901A>T (p.Thr1301Ser)

gnomAD frequency: 0.00001  dbSNP: rs779899032

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698638	SCV000827318	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1301 of the BRCA2 protein (p.Thr1301Ser). This variant is present in population databases (rs779899032, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 576201). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Color Diagnostics, LLC DBA Color Health	RCV000772743	SCV000906071	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293520	SCV001482111	uncertain significance	not specified	2021-02-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3901A>T (p.Thr1301Ser) 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 allele was found at a frequency of 9.9e-06 in 201666 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3901A>T has been reported in the literature in an individual affected with breast cancer (Tung_2014). This report 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. Two 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.
Ambry Genetics	RCV000772743	SCV002623929	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-09	criteria provided, single submitter	clinical testing	The p.T1301S variant (also known as c.3901A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 3901. The threonine at codon 1301 is replaced by serine, an amino acid with similar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000772743	SCV003848513	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).