Submissions for variant NM_000059.3(BRCA2):c.2412A>G (p.Glu804=) (rs587780866)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495335	SCV000579000	likely benign	Breast-ovarian cancer, familial 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/).
GeneDx	RCV000123952	SCV000167343	benign	not specified	2014-02-20	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.
Ambry Genetics	RCV000163719	SCV000214293	likely benign	Hereditary cancer-predisposing syndrome	2014-07-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001086553	SCV000261242	benign	Hereditary breast and ovarian cancer syndrome	2020-11-16	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000163719	SCV000688753	likely benign	Hereditary cancer-predisposing syndrome	2017-09-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123952	SCV000694605	likely benign	not specified	2019-02-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2412A>G alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 275088 control chromosomes, predominantly at a frequency of 0.00082 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.2412A>G has been reported in the literature in an individual affected with contralateral breast cancer (Borg_2010). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported in our internal database (BRCA1 whole gene deletion), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000495335	SCV000785297	likely benign	Breast-ovarian cancer, familial 2	2017-06-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587995	SCV000887773	benign	not provided	2018-11-12	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000495335	SCV001273110	uncertain significance	Breast-ovarian cancer, familial 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV001115157	SCV001273111	uncertain significance	Fanconi anemia, complementation group D1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000587995	SCV000591807	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Glu804= variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Borg_2010_20104584). The variant was also identified in the following databases: dbSNP (ID: rs587780866) as “With other allele”, ClinVar (as likely benign, reviewed by an expert panel), Clinvitae (4x), COGR (as likely benign by a consensus of 3 clinical labs), AND UMD-LSDB (2x as uncertain significance). The variant was not identified in Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 30 of 275088 chromosomes at a frequency of 0.000109 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations including “Other” in 2 of 6412 chromosomes (freq: 0.000312), and Latino in 28 of 34052 chromosomes (freq: 0.000822); it was not observed in the African, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Glu804= 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. 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicted a greater than 10% difference in splicing; one altered 5' and one 3’ splice site. 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.