Submissions for variant NM_007294.4(BRCA1):c.1096G>C (p.Asp366His)

dbSNP: rs1289961661

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000579920	SCV000682935	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 366 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 individuals affected with pancreatic cancer and breast or ovarian cancer (PMID: 29470806, 32255556). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302591	SCV001491805	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 366 of the BRCA1 protein (p.Asp366His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer and/or pancreatic cancer (PMID: 29470806, 32255556). ClinVar contains an entry for this variant (Variation ID: 489705). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 32546644). 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.
Ambry Genetics	RCV000579920	SCV002738540	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-16	criteria provided, single submitter	clinical testing	The p.D366H variant (also known as c.1096G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 1096. The aspartic acid at codon 366 is replaced by histidine, an amino acid with similar properties. This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000579920	SCV003846174	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).
Neuberg Centre For Genomic Medicine, NCGM	RCV003338671	SCV004047590	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The missense variant c.1096G>C (p.Asp366His) in BRCA2 gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Asp366His variant is novel (not in any individuals) in gnomAD exomes and 1000 Genomes. The amino acid Asp at position 366 is changed to a His changing protein sequence and it might alter its composition and physicochemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).
All of Us Research Program, National Institutes of Health	RCV003338671	SCV004818372	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 366 of the BRCA1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.