Submissions for variant NM_000059.4(BRCA2):c.9605C>T (p.Pro3202Leu)

dbSNP: rs397507432

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196044	SCV000253063	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000216276	SCV000275485	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	The p.P3202L variant (also known as c.9605C>T), located in coding exon 25 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9605. The proline at codon 3202 is replaced by leucine, an amino acid with similar properties. This alteration was observed in 1/7051 unselected female breast cancer patients and was not observed in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was reportedly detected in conjunction with a pathogenic mutation in the BRCA2 gene in two separate cases recorded in the Universal Mutation Database (http://www.umd.be/BRCA2); however, the phase (whether in cis or trans) is not known, nor are the case phenotypes. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other 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.
Counsyl	RCV000031837	SCV000488573	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001703442	SCV000527617	likely benign	not provided	2019-02-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25348012, 22505045, 30287823)
Color Diagnostics, LLC DBA Color Health	RCV000216276	SCV000911442	benign	Hereditary cancer-predisposing syndrome	2016-10-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436771	SCV000916937	likely benign	not specified	2021-07-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9605C>T (p.Pro3202Leu) 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 has been shown in functional studies to have no impact on splicing (Houdayer_2012). The variant allele was found at a frequency of 4e-06 in 251406 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9605C>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least one Japanese individual affected with breast cancer (example Momozawa_2018) and as a neutral missense variant in an individual with luminal breast tumor who also carried BRCA2 c.1306A>T (p.K436X) (example, Manie_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in the UMD database and in the literature (UMD database-BRCA2 c.4022C>A, p.Ser1341*; BRCA2 c.8331+2T>C; Manie_2016, BRCA2 c.1306A>T, p.K436*), providing supporting evidence for a benign role. Five 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 (benign, n=1; likely benign, n=2; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000031837	SCV004846196	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031837	SCV000054445	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing