Submissions for variant NM_000059.4(BRCA2):c.3672C>T (p.Gly1224=)

gnomAD frequency: 0.00001  dbSNP: rs587780650

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495475	SCV000578734	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/).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085375	SCV000166166	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000164840	SCV000215523	likely benign	Hereditary cancer-predisposing syndrome	2014-06-20	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.
Color Diagnostics, LLC DBA Color Health	RCV000164840	SCV000683570	likely benign	Hereditary cancer-predisposing syndrome	2015-07-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000495475	SCV000785874	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755870	SCV000883500	likely benign	not provided	2018-02-01	criteria provided, single submitter	clinical testing	The BRCA2 c.3672C>T; p.Gly1224Gly variant (rs587780650), to our knowledge, is not reported in the medical literature but is reported as likely benign by multiple labs in ClinVar (Variation ID: 135797). Additionally, another variant at this nucleotide position (c.3672C>G; p.Gly1224Gly) has also been reported as likely benign to ClinVar (Variation ID: 481605). The c.3672C>T variant is found in the general population at an overall frequency of 0.003% (1/30934 alleles) in the Genome Aggregation Database. This is a synonymous change, the nucleotide is weakly conserved, and computational algorithms (SpliceSiteFinder-like, MaxEntScan, NNSplice, GeneSplicer, Human Splicing Finder) do not predict that this variant impacts splicing. Based on the above information, this variant is considered likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755870	SCV000889024	likely benign	not provided	2022-02-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770720	SCV000902199	likely benign	Breast and/or ovarian cancer	2017-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507541	SCV000918880	likely benign	not specified	2020-11-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000755870	SCV001885436	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000755870	SCV001551167	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Gly1224= variant was not identified in the literature nor was it identified in the COGR, COSMIC, MutDB, UMD, LOVD 3.0, BIC, ARUP Laboratories BRCA Mutations Database or Zhejiang University database. The variant was identified in dbSNP (ID: rs587780650) as "With Likely benign allele", and in Clinvar database (classified as likely benign by Invitae, Ambry Genetics and 4 other submitters). The variant was identified in control databases in 1 of 30934 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the “Other” population in 1 of 978 chromosomes (freq: 0.001); it was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gly1224= 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004542925	SCV004770714	likely benign	BRCA2-related disorder	2020-01-10	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).