Submissions for variant NM_000059.4(BRCA2):c.9403C>T (p.Leu3135Phe)

gnomAD frequency: 0.00001  dbSNP: rs55704151

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219010	SCV000275835	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The p.L3135F variant (also known as c.9403C>T), located in coding exon 24 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9403. The leucine at codon 3135 is replaced by phenylalanine, an amino acid with highly similar 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.
GeneDx	RCV000215156	SCV000278889	uncertain significance	not provided	2016-07-26	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9403C>T at the cDNA level, p.Leu3135Phe (L3135F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 9631C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu3135Phe 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 Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Leu3135Phe occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Leu3135Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000219010	SCV000684061	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 3135 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. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 1.1193, respectively (PMID: 31131967). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705106	SCV000834088	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 3135 of the BRCA2 protein (p.Leu3135Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 231858). 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.
Baylor Genetics	RCV003475020	SCV004211912	uncertain significance	Familial cancer of breast	2023-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000238693	SCV004846169	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 3135 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. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 1.1193, respectively (PMID: 31131967). 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	RCV004767175	SCV005380812	uncertain significance	not specified	2024-08-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000238693	SCV000297578	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-02-28	no assertion criteria provided	clinical testing