Submissions for variant NM_000059.4(BRCA2):c.8647C>T (p.Pro2883Ser)

gnomAD frequency: 0.00001  dbSNP: rs80359122

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045590	SCV000073603	likely benign	Hereditary breast ovarian cancer syndrome	2023-08-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001703441	SCV000512393	likely benign	not provided	2021-02-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25382762, 20104584, 19043619, 21520273, 10923033)
Ambry Genetics	RCV000567301	SCV000668605	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The p.P2883S variant (also known as c.8647C>T), located in coding exon 20 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8647. The proline at codon 2883 is replaced by serine, an amino acid with similar properties. This variant was detected and reported as an unclassified variant in a unilateral breast cancer patient in a cohort of 705 contralateral and 1398 unilateral breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40). In a study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted neutral (Karchin R et al. Cancer Inform. 2008; 6:203-16). 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.
Color Diagnostics, LLC DBA Color Health	RCV000567301	SCV000689143	likely benign	Hereditary cancer-predisposing syndrome	2017-05-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417546	SCV000695168	likely benign	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8647C>T (p.Pro2883Ser) 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 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8647C>T has been reported in the literature in at-least one individual affected with unilateral breast cancer ((example, Borg_2010, Capanu_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA1 c.2722G>T, p.Glu908Ter; BRCA1 exon13ins6kb), providing supporting evidence for a benign role. At least one publication reports experimental evidence reporting no effect on splicing, however, this does not allow convincing conclusions about the variant functional effect (example, Acedo_2015). Another likelihood ratio based analysis has predicted the variant to have a neutral impact (example, Karchin_2008). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four reported a classification as likely benign. Based on the evidence outlined above, the variant was re-classified as likely benign.
Mendelics	RCV000031758	SCV001139223	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000567301	SCV002531963	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-24	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031758	SCV000054366	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2013-08-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031758	SCV000147428	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001703441	SCV001951748	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001703441	SCV001970282	likely benign	not provided		no assertion criteria provided	clinical testing