Submissions for variant NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del)

dbSNP: rs1064793600

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000515764	SCV000920456	pathogenic	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability > 0.99 (0.992)
GeneDx	RCV000481569	SCV000566567	uncertain significance	not provided	2016-09-14	criteria provided, single submitter	clinical testing	This in-frame deletion of 3 nucleotides in MSH6 is denoted c.1618_1620delCTT at the cDNA level and p.Leu540del (L540del) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTT[CTT]AGCC. This deletion of a single Leucine residue occurs at a position that is conserved across species and is located in the MSH2 binding region and MutS domain II (Kariola 2002, Terui 2013). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Leu540del to be a variant of uncertain significance.
Ambry Genetics	RCV000491419	SCV000580277	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-21	criteria provided, single submitter	clinical testing	The c.1618_1620delCTT variant (also known as p.L540del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame CTT deletion at nucleotide positions 1618 to 1620. This results in the in-frame deletion of a leucine at codon 540. This alteration has been identified in the germline of individuals whose Lynch-associated tumors displayed isolated loss of MSH6 on immunohistochemistry (IHC) and/or high microsatellite instability (MSI-H) (Dámaso E et al. Cancers (Basel), 2020 Jul;12; Ambry internal data). This alteration was detected as homozygous in a patient with features consistent with constitutional mismatch repair deficiency (Personal communication with external laboratory). This alteration was classified as pathogenic by one study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). Based on an internal structural assessment, this alteration disrupts the structure of the connector domain (Warren JJ et al. Mol Cell, 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000515764	SCV000611879	pathogenic	Lynch syndrome	2018-03-28	criteria provided, single submitter	research	The MSH6 variant designated as NM_000179.2:c.1618_1620del (p.Leu540del) is classified as pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood of 1.838 to 1, which supports pathogenicity (Thompson et al, 2003, PMID:12900794). In addition, endometrial and colorectal tumors from an affected individual in the family contained the germline MHS6 p.Leu540del variant. Each tumor had microsatellite instability and had a different independent second heterozygous pathogenic mutation in MSH6. Each of these observations supports classification of pathogenicity. In addition, this variant has previously been reported in two MSI high tumors with lack of MSH6 staining on IHC (http://www.umd.be/). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives over 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH6 function and increase cancer risk. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Invitae	RCV000685620	SCV000813105	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-03	criteria provided, single submitter	clinical testing	This variant, c.1618_1620del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Leu540del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome and/or constitutional mismatch repair deficiency syndrome (PMID: 30374176, 32635641, 34787334; external communication). ClinVar contains an entry for this variant (Variation ID: 419037). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 32635641). For these reasons, this variant has been classified as Pathogenic.
GeneKor MSA	RCV000491419	SCV000822060	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001543126	SCV001761645	likely pathogenic	Lynch syndrome 5	2021-07-26	criteria provided, single submitter	clinical testing	The MSH6 c.1618_1620del (p.Leu540del) change is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). The change results in the deletion of a single leucine residue in the MSH2 binding region and MutS domain II (PM4). This variant has been reported as heterozygous in individuals with Lynch syndrome (PS4; PMID: 32635641, 30374176) and as homozygous in an individual with CMMRD (ClinVar Accession: SCV000813105.3). The colon and endometrial tumors of one individual carrying this germline alteration harbored unique second hits in MSH6 and microsatellite instability (PMID: 30374176). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PS4, PM2_supporting, PM4.
Myriad Genetics, Inc.	RCV001543126	SCV004185573	likely pathogenic	Lynch syndrome 5	2023-08-15	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003463988	SCV004196371	likely pathogenic	Endometrial carcinoma	2021-06-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491419	SCV004357603	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-28	criteria provided, single submitter	clinical testing	This variant causes a deletion of one amino acid in exon 4 of the MSH6 protein. This variant has been observed in several individual affected with Lynch sydrome-associated cancer (PMID: 32635641; ClinVar SCV000580277.5), with tumors that exhibited microsatellite instability and/or loss of MSH6 proteins by immunohistochemistry analyses. RNA analysis demonstrated the presence of an aberrant transcript at low proportion alongside the full-length transcript (PMID: 32635641). This variant has also been observed in homozygous state in individuals affected with autosomal recessive constitutional mismatch mismatch repair deficiency (PMID: 34787334; ClinVar SCV000813105.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000515764	SCV004834317	likely pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This variant causes a deletion of one amino acid in exon 4 of the MSH6 protein. This variant has been observed in several individual affected with Lynch sydrome-associated cancer (PMID: 32635641; ClinVar SCV000580277.5), with tumors that exhibited microsatellite instability and/or loss of MSH6 proteins by immunohistochemistry analyses. RNA analysis demonstrated the presence of an aberrant transcript at low proportion alongside the full-length transcript (PMID: 32635641). This variant has also been observed in homozygous state in individuals affected with autosomal recessive constitutional mismatch mismatch repair deficiency (PMID: 34787334; ClinVar SCV000813105.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.