Submissions for variant NM_000059.4(BRCA2):c.6117A>C (p.Leu2039Phe)

gnomAD frequency: 0.00001  dbSNP: rs1566233950

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685899	SCV000813399	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-04	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 566156). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2039 of the BRCA2 protein (p.Leu2039Phe).
Ambry Genetics	RCV001024910	SCV001187005	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	The p.L2039F variant (also known as c.6117A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 6117. The leucine at codon 2039 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00027 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083). This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193357	SCV001362119	uncertain significance	not specified	2019-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6117A>C (p.Leu2039Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250942 control chromosomes. In the Japanese population, the variant was identified in at-least 3 out of 12,490 unaffected controls but not in any cases of breast cancer (Momozawa_2018). The available data on variant occurrences in the general population as well as in the Japanese subpopulation are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6117A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been reported at our laboratory (BRCA1 c.188T>A, p.Leu63*), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001024910	SCV003850948	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).