Submissions for variant NM_007294.4(BRCA1):c.2207A>C (p.Glu736Ala)

gnomAD frequency: 0.00001  dbSNP: rs397507196

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131694	SCV000186730	likely benign	Hereditary cancer-predisposing syndrome	2018-05-21	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.
GeneDx	RCV000589110	SCV000512292	likely benign	not provided	2020-01-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22753008, 21990134, 24728327, 18824701, 18779604, 31131967)
Invitae	RCV001080309	SCV000560220	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000120271	SCV000602705	likely benign	not specified	2016-11-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131694	SCV000911191	benign	Hereditary cancer-predisposing syndrome	2016-01-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589110	SCV001133519	likely benign	not provided	2022-08-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120271	SCV001338500	likely benign	not specified	2023-01-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2207A>C (p.Glu736Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250714 control chromosomes (gnomAD v2, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2207A>C has been reported in the literature in an individual with an unspecified cancer diagnosis without evidence of cosegregation (Kurian_2008), and also, in a breast cancer tumor where it was interpreted as neutral by the authors (Spearman_2008). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as benign/likely benign. Furthermore, a publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of likely benign based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of breast tumor pathology, co-occurrence, family history and bioinformatic predictions. We have previously classified this variant as a VUS-possibly benign, however, all emerging consensus seems to point towards a benign outcome. Based on review of the evidence spanning 7 years (2016-2023), as outlined above, the variant was re-classified as likely benign.
Sharing Clinical Reports Project (SCRP)	RCV000031036	SCV000053630	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-02-01	no assertion criteria provided	clinical testing
ITMI	RCV000120271	SCV000084423	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357499	SCV001552985	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu736Ala variant was identified in the literature and classified using a multifactorial probability based model as likely benign, however the frequency of this variant in an affected population was not provided (Lindor_2012_21990134). The variant was also identified in dbSNP (ID: rs397507196) as “With Likely benign allele”, ClinVar (as likely benign by Ambry, GeneDx, Invitae, and ARUP, and as benign by SCRP), Clinvitae (4x), GeneInsight-COGR, LOVD 3.0 (2x), ARUP Laboratories (as likely benign) databases. The variant was not identified in Cosmic, MutDB, UMD-LSDB, BIC Database, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 1 of 30964 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 1 of 1620 chromosomes (freq: 0.000617), while the variant was not observed in the African, Other, Latino, European (Non-Finnish), Ashkenazi Jewish, European (Finnish) and South Asian populations. The p.Glu736 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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.