Submissions for variant NM_000059.4(BRCA2):c.9690A>T (p.Leu3230Phe)

gnomAD frequency: 0.00001  dbSNP: rs80359238

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045886	SCV000073899	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-09	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 3230 of the BRCA2 protein (p.Leu3230Phe). This variant is present in population databases (rs80359238, gnomAD 0.01%). This missense change has been observed in individual(s) with personal and/or family history of breast and ovarian cancer (PMID: 32068069). ClinVar contains an entry for this variant (Variation ID: 52891). 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.
Ambry Genetics	RCV000131275	SCV000186243	likely benign	Hereditary cancer-predisposing syndrome	2024-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508027	SCV000600873	uncertain significance	not provided	2024-01-17	criteria provided, single submitter	clinical testing	The BRCA2 c.9690A>T (p.Leu3230Phe) variant has been reported in the published literature in in individuals with breast cancer (PMID: 32068069 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). This variant has also been identified in reportedly healthy individuals (PMID: 32467295 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.000008 (2/250142 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools (i.e., MutationTaster and PolyPhen-2) for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000131275	SCV000684085	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 3230 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250142 chromosomes 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.
Counsyl	RCV000114154	SCV000785304	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155054	SCV003844298	uncertain significance	not specified	2023-02-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9690A>T (p.Leu3230Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250142 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9690A>T has been reported in the literature in an individual who underwent cancer panel testing however, authors classified the variant as VUS (exampe: Kwong_2020). These report(s) 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 annd all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004803947	SCV004846219	uncertain significance	BRCA2-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 3230 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 32068069, 33471991) and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008789). This variant has been identified in 2/250142 chromosomes 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114154	SCV000147699	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing