Submissions for variant NM_007294.4(BRCA1):c.1819A>G (p.Lys607Glu)

dbSNP: rs80357220

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240791	SCV000265877	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000580306	SCV000682987	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-29	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 607 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). 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 been reported in individuals affected with breast cancer (PMID: 27257965). This variant has also been identified in 1/251010 chromosomes 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.
Ambry Genetics	RCV000580306	SCV002712018	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-21	criteria provided, single submitter	clinical testing	The p.K607E variant (also known as c.1819A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1819. The lysine at codon 607 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in 2/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS One, 2016 Jun;11:e0156789). This amino acid position is well 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000580306	SCV003849715	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).
Myriad Genetics, Inc.	RCV003316160	SCV004020246	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Invitae	RCV003644930	SCV004509447	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-12-08	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: 224430). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 27257965). This variant is present in population databases (rs80357220, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 607 of the BRCA1 protein (p.Lys607Glu).