Submissions for variant NM_007294.4(BRCA1):c.398G>A (p.Arg133His)

gnomAD frequency: 0.00003  dbSNP: rs80357357

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128888	SCV000172747	likely benign	Hereditary cancer-predisposing syndrome	2019-05-03	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	RCV001719703	SCV000517330	likely benign	not provided	2019-11-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15385441, 29625052, 23161852, 25348012, 29470806, 29176636, 27930734, 31131967, 30617304)
Color Diagnostics, LLC DBA Color Health	RCV000128888	SCV000909412	likely benign	Hereditary cancer-predisposing syndrome	2017-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000443460	SCV000916766	uncertain significance	not specified	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.398G>A (p.Arg133His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251442 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.398G>A has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Santonicito_2020, Dorling_2021), however it was also found in healthy control individuals (e.g. Momozawa_2018, Dong_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated similar homology-directed recombination to the wild-type protein, slightly decreased E3 ligase activity and decreased interaction with Rack1 and impaired centrosome localization (Towler_2013, Starita_2015, Yoshino_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=5) or VUS (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000031138	SCV001140637	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001479032	SCV001683322	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128888	SCV002538252	likely benign	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031138	SCV000053737	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031138	SCV000145279	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-22	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353645	SCV000591263	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Arg133His variant was not identified in the literature nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, ClinVar, or BIC databases. It is listed in the dbSNP database (rs#80357357) but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The p.Arg133 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg133His variant may impact the protein. However, this information is not predictive enough to assume 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 unknown significance.