Submissions for variant NM_007294.4(BRCA1):c.1121C>T (p.Thr374Ile)

dbSNP: rs80357235

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575806	SCV000661016	uncertain significance	Hereditary cancer-predisposing syndrome	2016-03-22	criteria provided, single submitter	clinical testing	The p.T374I variant (also known as c.1121C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1121. The threonine at codon 374 is replaced by isoleucine, an amino acid with similar properties. This alteration (designated 1240C>T) has been identified in a Spanish breast cancer family (Díez O et al, Int. J. Cancer 1999 Nov; 83(4):465-9). This variant was previously reported in the SNPDatabase as rs80357235, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 225000 alleles tested) in our clinical cohort. This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358702	SCV001554523	uncertain significance	not specified	2021-03-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1121C>T (p.Thr374Ile) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251220 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1121C>T has been reported in the literature under a legacy nomenclature of 1240C>T in a family with individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Diez_1999). In this family it was reported to co-occur in cis with another adjacent truncation variant reported as 1241delC. The PTT (protein truncation testing) identified a truncated protein product in the probands sample. She had been diagnosed as having BC at 28 years of age. This report does not provide unequivocal conclusions about association of the variant in isolation with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no conclusive experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV002514227	SCV003441972	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-07-10	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 54136). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10508480). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 374 of the BRCA1 protein (p.Thr374Ile).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575806	SCV003846155	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111554	SCV000144016	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-01-15	no assertion criteria provided	clinical testing