Submissions for variant NM_007294.4(BRCA1):c.3620A>T (p.Lys1207Met)

dbSNP: rs1555587402

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000535503	SCV000635908	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1207 of the BRCA1 protein (p.Lys1207Met). 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: 462616). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency).
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157704	SCV003846575	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	RCV001357923	SCV001553528	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Lys1207Met variant was not identified in the literature nor was it identified in dbSNP, GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC Database, ARUP Laboratories, or Zhejiang University Database. The variant was identified in ClinVar (classified as uncertain significance by Invitae). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Lys1207 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 uncertain significance.