Submissions for variant NM_007294.4(BRCA1):c.3221G>C (p.Arg1074Thr)

gnomAD frequency: 0.00001  dbSNP: rs786202155

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164826	SCV000215509	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.R1074T variant (also known as c.3221G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 3221. The arginine at codon 1074 is replaced by threonine, an amino acid with similar properties. This alteration was previously reported in 0/1398 unilateral breast cancer cases and 1/705 bilateral breast cancer cases in a population based study (Borg A et al. Hum. Mutat. 2010 Mar; 31(3):E1200-40; Capanu M et al. Genet. Epidemiol., 2011 Jul;35:389-97). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000205205	SCV000260402	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1074 of the BRCA1 protein (p.Arg1074Thr). This variant is present in population databases (rs786202155, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 185414). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. 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.
Counsyl	RCV000662432	SCV000784888	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164826	SCV000909314	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-22	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164826	SCV003850776	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
GeneDx	RCV003233478	SCV003930991	uncertain significance	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Observed in an individual with breast cancer (Borg et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3340G>C; This variant is associated with the following publications: (PMID: 15343273, 32377563, 29884841, 20104584, 21520273)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398837	SCV004122957	uncertain significance	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3221G>C (p.Arg1074Thr) 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 250402 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3221G>C has been reported in the literature in individuals affected with Breast cancer (examples: Borg_2010 and Capanu_2011). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 20104584, 21520273). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=5) as well as likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.