Submissions for variant NM_007294.4(BRCA1):c.216C>G (p.Ser72Arg)

gnomAD frequency: 0.00001  dbSNP: rs80356967

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564950	SCV000668510	likely benign	Hereditary cancer-predisposing syndrome	2021-04-19	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590511	SCV000698926	uncertain significance	not provided	2016-05-10	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.216C>G (p.Ser72Arg) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The variant was found in 1/121250 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It was reported in HBOC spectrum patients, however without strong evidence for pathogenicity. Functional studies demonstrated the variant to be proficient in HDR and defective in E3 ligase activity. However, studies reporting BRCA1 tumor suppression as being dependent on the ablation of phosphoprotein binding but not on its E3 ligase activity pose a challenge in using this as a measure of molecular pathogenesis in-vivo (Shakya_2011). A clinical diagnostic laboratory classifies variant as Uncertain. Considering all evidence, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590511	SCV000887638	uncertain significance	not provided	2018-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV001371073	SCV001567626	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 72 of the BRCA1 protein (p.Ser72Arg). This variant is present in population databases (rs80356967, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 16403807, 25823446). ClinVar contains an entry for this variant (Variation ID: 182123). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 16403807, 25823446). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV001072676	SCV004043182	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Brotman Baty Institute, University of Washington	RCV001072676	SCV001238102	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro