Submissions for variant NM_000179.3(MSH6):c.3725G>A (p.Arg1242His)

dbSNP: rs63750119

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129081	SCV000183784	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.R1242H pathogenic mutation (also known as c.3725G>A), located in coding exon 8 of the MSH6 gene, results from a G to A substitution at nucleotide position 3725. The arginine at codon 1242 is replaced by histidine, an amino acid with highly similar properties. This mutation was detected in trans with a pathogenic MSH6 mutation in an individual whose clinical presentation was consistent with CMMR-D, with isolated absence of MSH6 in both tumor and normal tissue by immunohistochemistry (IHC; LaDuca H et al. Genet. Med. 2014;16(11):830-7). This pathogenic mutation has also been reported as a homozygous, germline finding in two siblings diagnosed with a high grade glioma in childhood (Guerrini-Rousseau L et al. Neurooncol Adv. Dec;1:vdz033). In addition, this mutation has been identified in multiple probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH6 expression by IHC (Ambry internal data). Based on an internal structural analysis, this mutation is anticipated to result in a significant decrease in structural stability (Warren JJ et al. Mol. Cell. 2007 May;26:579-92). An in-frame deletion of the arginine residue at codon 1242 has been detected in multiple families meeting diagnostic criteria for Lynch syndrome, supporting the pathogenicity of alterations at this position (Roncari B et al. Clin Genet. 2007 Sep;72(3):230-7; LaDuca H et al. Genet. Med. 2014 Nov; 16(11):830-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001034637	SCV000283817	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1242 of the MSH6 protein (p.Arg1242His). This variant is present in population databases (rs63750119, gnomAD 0.006%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency and/or individuals who were referred for hereditary cancer testing (PMID: 24763289, 28514183, 31204389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140866). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000485282	SCV000568732	likely pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene referred for genetic testing at Genedx and in the published literature (LaDuca et al., 2014); This variant is associated with the following publications: (PMID: 24763289, 25370038, 17531815, 25111426, 29596542, 21120944, 23729658, 30787465, 31391288, 32642664, 28514183, 17718861, 29922827, 31204389, 30128536, 29915797)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000230170	SCV000695884	likely pathogenic	Hereditary nonpolyposis colon cancer	2020-07-28	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3725G>A (p.Arg1242His) results in a non-conservative amino acid change located in the MutS, C-terminal domain (IPR000432) of the encoded protein sequence, which is comprised of the ATPase domain and the HTH (helix-turn-helix) domain, the latter being involved in dimer contacts. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245952 control chromosomes (gnomAD). c.3725G>A has been reported in the literature in individuals affected with Lynch Syndrome (LS) (LaDuca 2014, Espenschied 2017). It was reported in two patients (brothers) in homozygosity who had symptoms characteristic of constitutive mismatch repair deficiency (CMMRD) syndrome (UMD data) and isolated lack of MSH6 staining on IHC, indicating causality. Another individual was also reported with a phenotype suggestive of CMMRD, who also carried a likely pathogenic MSH6 variant (c.3G>T (p.Met1Ile)) in trans, with the lack of MSH6 staining in the tumor as well as in normal tissue (InSiGHT data), consistent with biallelic loss of MSH6. A further patient with clinical features suggestive of CMMRD has been reported by Ambry Genetics (Dalton 2015). These data indicate that the variant is likely to be associated with disease. Of note, the variant was identified along with another co-occurring pathogenic variant in the ATM gene (c. 7271T>G (p.V2424G)) in a 27 year old female tested at our laboratory with personal and family history of Breast Cancer. However, the association of MSH6 c.3725G>A with LS remains unclear as no clinical information on two other carriers of this variant (father, sister) were available at the time of evaluation. Six 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl	RCV000663091	SCV000786188	likely pathogenic	Lynch syndrome 5	2018-03-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000485282	SCV000885717	likely pathogenic	not provided	2018-04-26	criteria provided, single submitter	clinical testing	The c.3725G>A; p.Arg1242His variant (rs63750119) has been described in the homozygous state in two brothers with gliomas, one of whom also had cafe-au-lait macules (see link for UMD database, Grandval 2013). This variant is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 140866) and is observed in only 1 out of 245952 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1242 is highly conserved within domain V of the MutS domain (Warren 2007) and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. Additionally, another variant at this codon (p.Arg1242Ser) has been reported in individuals with colorectal cancer (O’Leary 2014). Based on available information, this variant is considered likely pathogenic. References: Link to UMD database: http://139.124.156.133/4D_molecules/UMD175743.html Grandval P et al. UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. O’Leary E et al. A multi-disciplinary cancer program enhances hereditary colorectal cancer detection. Am J Digest Dis 2014;1(1):62-66. Warren J et al. Structure of the human MutSalpha DNA lesion recognition complex. Mol Cell. 2007;26:579–592.
Color Diagnostics, LLC DBA Color Health	RCV000129081	SCV000903541	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1242 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state in two brothers affected with constitutional mismatch repair deficiency (PMID: 32642664), and in a 23 year old individual affected with colorectal cancer and polyps who carried another MSH6 pathogenic variant in trans (LOVD database). This variant has also been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 29915797, 36425062; ClinVar SCV000183784.8; Insight database), breast cancer (PMID: 30128536), and in individuals who underwent hereditary cancer multigene panel testing (PMID: 24763289, 28514183). In addition, different variants that affect the amino acid at the same position (p.Arg1242del and p.Arg1242Ser) are considered to be disease-causing (ClinVar variation ID: 89450, 89449), suggesting that arginine at this position is important for protein structure and function. This variant has been identified in 1/251180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485282	SCV002046207	likely pathogenic	not provided	2022-10-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251180 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 35014770 (2022)) and in several individuals who were referred for hereditary cancer testing (PMID: 24763289, 28514183). It was also reported as a homozygous variant in 2 siblings affected with high grade gliomas in the published literature (PMID: 32642664 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Revvity Omics, Revvity	RCV000485282	SCV003833110	likely pathogenic	not provided	2022-08-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663091	SCV004019005	likely pathogenic	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 32642664]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003460886	SCV004198102	likely pathogenic	Endometrial carcinoma	2022-12-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997478	SCV004835121	pathogenic	Lynch syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1242 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state in two brothers affected with constitutional mismatch repair deficiency (PMID: 32642664), and in a 23 year old individual affected with colorectal cancer and polyps who carried another MSH6 pathogenic variant in trans (LOVD database). This variant has also been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 29915797, 36425062; ClinVar SCV000183784.8; Insight database), breast cancer (PMID: 30128536), and in individuals who underwent hereditary cancer multigene panel testing (PMID: 24763289, 28514183). In addition, different variant that affect the amino acid at the same position (p.Arg1242del and p.Arg1242Ser) are considered to be disease-causing (ClinVar variation ID: 89450, 89449), suggesting that arginine at this position is important for protein structure and function. This variant has been identified in 1/251180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
GenomeConnect, ClinGen	RCV000485282	SCV000986867	not provided	not provided		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 10/26/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.