Submissions for variant NM_007294.4(BRCA1):c.1849A>G (p.Thr617Ala)

dbSNP: rs45564238

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130111	SCV000184941	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-10	criteria provided, single submitter	clinical testing	The p.T617A variant (also known as c.1849A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1849. The threonine at codon 617 is replaced by alanine, an amino acid with similar properties. This alteration was detected as a secondary finding in 1 out of 572 ClinSeq participants unselected for personal or family history of cancer who underwent exome sequencing; the clinical information for this particular individual was not provided (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91(1):97-108). This variant was also reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Counsyl	RCV000409706	SCV000487806	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416510	SCV000549285	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 617 of the BRCA1 protein (p.Thr617Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 41807). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
GeneDx	RCV000034729	SCV000567821	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	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); Observed in cases and controls in a breast cancer study (Dorling et al., 2021); Also known as 1968A>G; This variant is associated with the following publications: (PMID: 22703879, 30244837, 29884841, 15343273, 32377563, 33471991)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226173	SCV000698892	uncertain significance	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1849A>G (p.Thr617Ala) 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 251132 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1849A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The variant was detected in one individual in the FLOSSIES database (women 70+ years of age without cancer). ClinVar contains an entry for this variant (Variation ID: 41807). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130111	SCV000911431	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 617 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006481). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130111	SCV003849699	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).
All of Us Research Program, National Institutes of Health	RCV000409706	SCV004818274	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 617 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034729	SCV000043179	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.