Submissions for variant NM_000059.4(BRCA2):c.9812T>C (p.Leu3271Ser)

gnomAD frequency: 0.00001  dbSNP: rs397507436

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130205	SCV000185043	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-23	criteria provided, single submitter	clinical testing	The p.L3271S variant (also known as c.9812T>C), located in coding exon 26 of the BRCA2 gene, results from a T to C substitution at nucleotide position 9812. The leucine at codon 3271 is replaced by serine, an amino acid with dissimilar 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 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.
GeneDx	RCV000759695	SCV000293921	uncertain significance	not provided	2016-02-05	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9812T>C at the cDNA level, p.Leu3271Ser (L3271S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). Using alternate nomenclature, this variant would be defined as BRCA2 10040T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu3271Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu3271Ser occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within the Cyclin A binding domain (Esashi 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Leu3271Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457079	SCV000549704	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3271 of the BRCA2 protein (p.Leu3271Ser). This variant is present in population databases (rs397507436, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 38264). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759695	SCV000889192	uncertain significance	not provided	2023-10-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194062	SCV001363313	uncertain significance	not specified	2019-10-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9812T>C (p.Leu3271Ser) results in a non-conservative amino acid change located in the Cy (RxL)-binding motif (amino acids 3,269-3,271; Esashi_2005) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251370 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9812T>C has been reported in the literature in an individual affected with Breast Cancer (Tung_2015). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031847	SCV000054455	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-16	no assertion criteria provided	clinical testing