Submissions for variant NM_007294.4(BRCA1):c.203T>G (p.Ile68Arg)

dbSNP: rs80357116

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001315867	SCV000698886	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.203T>G (p.Ile68Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250382 control chromosomes. c.203T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one functional study reports experimental evidence evaluating an impact on protein function and showed a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 26727311, 30219179, 25823446). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001315867	SCV001506461	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with arginine at codon 68 of the BRCA1 protein (p.Ile68Arg). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 54445). Experimental studies have shown that this missense change impacts the function of the BRCA1 protein as measured by its E3 ligase activity in vitro (PMID: 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000590778	SCV001716316	uncertain significance	not provided	2020-03-30	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112002	SCV000144639	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112002	SCV001242550	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro