Submissions for variant NM_000059.4(BRCA2):c.9538C>T (p.Leu3180Phe)

gnomAD frequency: 0.00001  dbSNP: rs200598289

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165783	SCV000216528	likely benign	Hereditary cancer-predisposing syndrome	2024-04-11	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.
GeneDx	RCV000482475	SCV000567649	uncertain significance	not provided	2018-01-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9538C>T at the cDNA level, p.Leu3180Phe (L3180F) 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 9766C>T. This variant was detected in 1/2089 breast cancer cases and 2/1448 controls in a study of multi-ethnic Asian individuals (Lai 2017). BRCA2 Leu3180Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Leu3180Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000165783	SCV000684069	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 3180 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). A functional study showed this variant does not impact viability in Brca2 null mouse embryonic stem cells (PMID: 33314489). This variant has been observed in multiple individuals affected with breast cancer (PMID: 22921312, 26689913, 28222693, 32068069) and in a healthy individual (PMID: 27157322). In a large breast cancer case-control study, this variant was observed in 5/60466 cases and 0/53461 controls; p-value=0.065 (PMID: 3347199; Leiden Open Variation Database DB-ID BRCA2_005921). This variant has been identified in 10/251368 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	RCV000077472	SCV000785683	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482475	SCV000887969	uncertain significance	not provided	2020-12-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765145	SCV000896371	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001318855	SCV001509572	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153338	SCV003843615	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492371	SCV004240378	uncertain significance	Breast and/or ovarian cancer	2022-12-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077472	SCV004846186	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 3180 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). A functional study showed this variant does not impact viability in Brca2 null mouse embryonic stem cells (PMID: 33314489). This variant has been observed in multiple individuals affected with breast cancer (PMID: 22921312, 26689913, 28222693, 32068069) and in a healthy individual (PMID: 27157322). In a large breast cancer case-control study, this variant was observed in 5/60466 cases and 0/53461 controls; p-value=0.065 (PMID: 3347199; Leiden Open Variation Database DB-ID BRCA2_005921). This variant has been identified in 10/251368 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.
Sharing Clinical Reports Project (SCRP)	RCV000077472	SCV000109270	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077472	SCV000147663	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing