Submissions for variant NM_007294.4(BRCA1):c.3965A>G (p.Lys1322Arg)

dbSNP: rs80357042

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568090	SCV000665854	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-22	criteria provided, single submitter	clinical testing	The p.K1322R variant (also known as c.3965A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3965. The lysine at codon 1322 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site, however direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637586	SCV000759052	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-25	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1322 of the BRCA1 protein (p.Lys1322Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 481448). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Color Diagnostics, LLC DBA Color Health	RCV000568090	SCV001339855	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1322 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. Splice site prediction tools indicate that this variant may create a cryptic splice acceptor site in exon 10 altering the encoded protein. To our knowledge, RNA splicing prediction and impact and functional studies have not been reported for this variant. A multifactorial analysis has reported likelihood ratios based on co-occurrence with a pathogenic variant and family history of 1.0331 and 0.6418, respectively (PMID: 31131967). This variant has been identified in 1/251298 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193746	SCV001362814	uncertain significance	not specified	2019-07-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3965A>G (p.Lys1322Arg) results in a 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 allele was found at a frequency of 4e-06 in 251298 control chromosomes (gnomAD). 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.3965A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance, until additional information becomes available.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568090	SCV003849399	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003230546	SCV003926629	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-29	criteria provided, single submitter	clinical testing	a variant of uncertain significance was detected in the BRCA1 gene (p.Lys1322Arg).This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1322 of the BRCA1 protein (p.Lys1322Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This amino acid position is mild conserved( PhylP=3.2) . 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: 481448). In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480698	SCV004224363	uncertain significance	not provided	2023-03-07	criteria provided, single submitter	clinical testing	PM2
Myriad Genetics, Inc.	RCV003230546	SCV005897182	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-11-06	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].
BRCAlab, Lund University	RCV003230546	SCV004244020	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing