Submissions for variant NM_000059.4(BRCA2):c.9843A>G (p.Pro3281=)

gnomAD frequency: 0.00047  dbSNP: rs11571832

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112817	SCV000578008	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0019 (African), derived from ExAC (2014-12-17).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045906	SCV000073919	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000176715	SCV000167424	benign	not specified	2014-05-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112817	SCV000196030	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163358	SCV000213893	likely benign	Hereditary cancer-predisposing syndrome	2014-10-24	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.
Eurofins Ntd Llc (ga)	RCV000176715	SCV000228419	likely benign	not specified	2015-01-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000476571	SCV000541065	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163358	SCV000684094	likely benign	Hereditary cancer-predisposing syndrome	2015-07-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000112817	SCV000784932	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000176715	SCV002068840	likely benign	not specified	2019-07-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163358	SCV002532065	likely benign	Hereditary cancer-predisposing syndrome	2021-03-19	criteria provided, single submitter	curation
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112817	SCV000145722	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-10-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358433	SCV001554162	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Pro3281= variant was identified in 1 of 800 proband chromosomes (frequency: 0.001) from Nigerian individuals with breast cancer, unselected for age of onset and family history (Fackenthal 2012). The variant was also identified in dbSNP (ID: rs11571832) “With Uncertain significance, other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; classified as benign by GeneDx, Michigan Medical Genetics Labs (U of Michigan), Baylor Miraca Genetics Labs and Invitae; likely benign by Ambry Genetics and Emory Genetics; and uncertain significance by BIC), Clinivitae (6X), LOVD 3.0 (3X) and BIC database (1X). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, BIC Database, ARUP Laboratories, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 41 of 276990 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 33 of 24028 chromosomes (frequency: 0.001), Other in 1 of 6458 chromosomes (frequency: 0.0002), Latino in 6 of 34410 chromosomes (frequency: 0.0002), European Non-Finnish in 1 of 126516 chromosomes (frequency: 0.000008), . The p.Pro3281= variant is not expected to have clinical significance because it does not result in a change of amino acid and occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.