Submissions for variant NM_007294.4(BRCA1):c.3737C>A (p.Thr1246Asn)

dbSNP: rs878854949

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084868	SCV000289785	benign	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573048	SCV000673057	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	The p.T1246N variant (also known as c.3737C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 3737. The threonine at codon 1246 is replaced by asparagine, an amino acid with similar properties. This alteration was reported in two of 585 Slovak families with suspected HBOC and was seen in cis with the BRCA1 c.4065_4068del4 mutation in both families (Konecny M et al. Breast Cancer Res. Treat. 2011 Feb;126:119-30). This variant was also identified in a Turkish patient with premature ovarian insufficiency, but her family history of cancer was not reported, and authors did not conclude the significance of p.T1246N (Ylmaz NK et al. J Turk Ger Gynecol Assoc 2016 Jan;17:77-82). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	RCV000588711	SCV000699065	uncertain significance	not provided	2016-05-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3737C>A (p.Thr1246Asn) variant involves the alteration of a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "benign" outcome . This variant was not observed in controls (ExAC, 1000 Gs or ESP). A publication cites the variant in two affected individuals that co-occurred with another pathogenic BRCA1 variant, c.4065_4068delTCAA (p.Asn1355fsX10 - classified as pathogenic by LCA). This variant was not, to our knowledge, reported in reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS) - possibly benign."
Color Diagnostics, LLC DBA Color Health	RCV000573048	SCV000911682	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 1246 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two families affected with hereditary breast and ovarian cancer, who also carried a pathogenic variant in the same gene that could explain the observed disease (PMID: 21203900). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588711	SCV001133565	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 21203900 (2011) and 27403073 (2016)). Additionally, the variant has been reported in a study of BRCA1 and BRCA2 regions without essential functions that tolerate variation (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000588711	SCV002818041	uncertain significance	not provided	2022-12-30	criteria provided, single submitter	clinical testing	Observed in families with breast and/or ovarian cancer who also carried a BRCA1 pathogenic variant (Konecny et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3856C>A, p.Thr1246Asn; This variant is associated with the following publications: (PMID: 27403073, 29884841, 32377563, 21203900)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000573048	SCV003849840	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502901	SCV000591467	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Thr1246Asn variant was identified in 2 of 1170 proband chromosomes (frequency: 0.002) from Slovak families with hereditary breast or ovarian cancer (Konecny 2011); however, control chromosomes were not evaluated in this study, thus the prevalence of this variant in the general population could not be determined. The variant was detected in association with a pathogenic BRCA1 mutation (c.4065_4068del4) in both of these families, with the authors suggesting that this may be a haplotype (i.e. inherited together on the same chromosome). Of note, the p.Thr1246Asn variant and the c.4065_4068del4 mutation were also found to co-occur in the individual tested by our lab. The variant was not identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC or UMD databases. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Thr1246 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out 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.