Submissions for variant NM_000059.4(BRCA2):c.1167G>A (p.Pro389=)

gnomAD frequency: 0.00007  dbSNP: rs148607710

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000494918	SCV000578830	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics	RCV000163590	SCV000214150	likely benign	Hereditary cancer-predisposing syndrome	2014-09-04	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086938	SCV000260877	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000590259	SCV000333318	uncertain significance	not provided	2015-07-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000302173	SCV000512337	benign	not specified	2015-08-27	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.
Color Diagnostics, LLC DBA Color Health	RCV000163590	SCV000688697	benign	Hereditary cancer-predisposing syndrome	2016-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000302173	SCV000694515	likely benign	not specified	2020-11-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590259	SCV000885114	likely benign	not provided	2017-09-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590259	SCV000887750	benign	not provided	2023-01-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163590	SCV002533213	likely benign	Hereditary cancer-predisposing syndrome	2021-10-28	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000590259	SCV002585440	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000302173	SCV004027401	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000494918	SCV004846872	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356802	SCV001552067	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Pro389= variant was identified in 6 of 7082 proband chromosomes (frequency: 0.00085) from individuals or families with breast cancer and in 3 of 334 control chromosomes (frequency: 0.009) (Borg_2010, Ermolenko_2015, Kim_2006, Stegel_2011). The variant was also identified in dbSNP (ID: rs148607710) as “With other allele”, ClinVar (as likely benign reviewed by expert panel), Clinvitae (5x), COGR (as likely benign by COGR consensus), LOVD 3.0 (2x as uncertain significance), UMD-LSDB (5x as uncertain significance, co-occuring with a pathogenic BRCA1 variant p.Asn1355LysfsX10). The variant was not identified in Cosmic, MutDB, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 18 of 277030 chromosomes at a frequency of 0.000065 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.000042), Latino in 1 of 34398 chromosomes (freq: 0.000029), European (Non-Finnish) in 13 of 126618 chromosomes (freq: 0.000103), East Asian in 2 of 18866 chromosomes (freq: 0.000106), and South Asian in 1 of 30738 chromosomes (freq: 0.000033); but not observed in the Other, Ashkenazi Jewish, or European (Finnish) populations. The p.Pro389= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.
PreventionGenetics, part of Exact Sciences	RCV004535078	SCV004753781	likely benign	BRCA2-related disorder	2019-06-04	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).