Submissions for variant NM_000059.4(BRCA2):c.5723T>C (p.Leu1908Pro)

gnomAD frequency: 0.00001  dbSNP: rs80358797

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220622	SCV000277026	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	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.
Counsyl	RCV000031572	SCV000488491	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001689581	SCV000512371	likely benign	not provided	2020-11-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22711857)
Color Diagnostics, LLC DBA Color Health	RCV000220622	SCV000911110	benign	Hereditary cancer-predisposing syndrome	2017-02-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001486114	SCV001690564	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798048	SCV002043234	uncertain significance	Breast and/or ovarian cancer	2019-11-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468982	SCV002766537	likely benign	not specified	2022-11-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5723T>C (p.Leu1908Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 250898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5723T>C has been reported in the literature in individuals affected with Cutaneous Melanoma and Ovarian Cancer Syndrome without strong evidence for causality (Alsop_2012 and Johansson_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. However, at-least one instance of an apparently homozygous genotype in an individual with no features or family history of Fanconi Anemia has been observed at our laboratory, thereby supporting a non-actionable/benign outcome for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments VUS (n=2), Likely Benign (n=3) and Benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000220622	SCV003849050	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).
Sharing Clinical Reports Project (SCRP)	RCV000031572	SCV000054178	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-02-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031572	SCV000146678	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001689581	SCV001906373	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001689581	SCV001957773	likely benign	not provided		no assertion criteria provided	clinical testing