Submissions for variant NM_007194.4(CHEK2):c.937G>A (p.Val313Met)

gnomAD frequency: 0.00006  dbSNP: rs752302543

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000466569	SCV000550502	uncertain significance	Familial cancer of breast	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 313 of the CHEK2 protein (p.Val313Met). This variant is present in population databases (rs752302543, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 410041). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000582321	SCV000689749	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-22	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 313 of the CHEK2 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 Indian individuals affected with breast and/or ovarian cancer (PMID: 29470806). This variant has been identified in 15/251446 chromosomes (15/30612 South Asian 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.
Counsyl	RCV000466569	SCV000785787	uncertain significance	Familial cancer of breast	2017-11-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765619	SCV000896944	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582321	SCV001180558	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-26	criteria provided, single submitter	clinical testing	The p.V313M variant (also known as c.937G>A), located in coding exon 8 of the CHEK2 gene, results from a G to A substitution at nucleotide position 937. The valine at codon 313 is replaced by methionine, an amino acid with highly 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 alteration was also identified in a cohort of 481 Chinese breast cancer patients with family history of breast/ovarian cancer (Wang J et al. Cancer Med, 2019 May;8:2074-2084). This amino acid position is highly 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000466569	SCV004015287	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	The p.Val313Met variant located in coding exon 9 of the CHEK2 gene, results from a G to A substitution at nucleotide position 937. The valine at codon 313is replaced by methionine, This variant has been reported in two Indian individuals affected with breast and/or ovarian cancer (PMID: 29470806). This amino acid position is moderate conserved (PhyloP= 3.07). This variant not present in our local database nor was it identified in the Genome Aggregation Database The computational analyses (PolyPhen-2, SIFT, MutationTaster) suggest a high pathogenic impacts on the protein. ClinVar has an entry (410041) for this variant as uncertain significance submitted by five different diagnostic labs .. Since supporting evidence is limited at this time, this variant is classified as of uncertain significance.
Myriad Genetics, Inc.	RCV000466569	SCV004020146	uncertain significance	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.