Submissions for variant NM_000179.3(MSH6):c.1120_1122del (p.Lys374del)

gnomAD frequency: 0.00003  dbSNP: rs587781660

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129805	SCV000184616	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-15	criteria provided, single submitter	clinical testing	The c.1120_1122delAAG variant (also known as p.K374del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame AAG deletion between nucleotide positions 1120 and 1122. This results in the deletion of a lysine residue at codon 374. Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Warren JJ et al. Mol Cell. 2007 May;26:579-92). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000679213	SCV000279311	uncertain significance	not provided	2023-12-08	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Located in the critical mismatch binding domain (PMID: 17531815, 21120944); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233727	SCV000283701	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-25	criteria provided, single submitter	clinical testing	This variant, c.1120_1122del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Lys374del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587781660, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 141328). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV000129805	SCV000685167	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/31380 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	RCV000781582	SCV000919744	uncertain significance	not specified	2018-03-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1120_1122delAAG (p.Lys374del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 3.2e-05 in 30954 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.1120_1122delAAG in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679213	SCV001134389	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV001257481	SCV001434287	uncertain significance	Lynch syndrome 5	2020-01-31	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk. (No codes)
Genetic Services Laboratory, University of Chicago	RCV000781582	SCV002069690	uncertain significance	not specified	2021-04-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH6 gene demonstrated a three base pairs deletion in exon 4, c.1120_1122del. This in-frame deletion is predicted to result in the deletion of a amino acid residue at codon 374, p.Lys374del. This sequence change does not appear to have been previously described in individuals with MSH6-related disorders. This sequence change has been described in one non-Finnish European in the gnomAD database (rs587781660). Due to the lack of functional studies, the clinical significance of this sequence change remains unknown at this time.
Sema4, Sema4	RCV000129805	SCV002535594	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003997525	SCV004842969	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid, Lysine 374, in the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 34359559). This variant has been identified in 1/31380 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.
Baylor Genetics	RCV004567096	SCV005054967	uncertain significance	Endometrial carcinoma	2024-01-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739434	SCV000805837	uncertain significance	MSH6-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The MSH6 c.1120_1122delAAG variant is predicted to result in an in-frame deletion (p.Lys374del). Structural analysis of the MSH2 and MSH6 complex showed that this variant is present in the mismatch binding domain (domain 1, amino acids 362-518 of MSH6) and variants leading to alterations of this region may lead to abnormal protein function/stability (Warren et al. 2007. PubMed ID: 17531815). This variant was also reported in 1 carrier among prospective index cases in a nation-wide study of hereditary breast and ovarian cancer families with a predicted pathogenic variant (Table S3, Lesueur et al. 2021. PubMed ID: 34359559). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141328/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.