2-47799092-T-C

Position:

• chr2-47799092-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000179.3(MSH6):​c.1109T>C​(p.Leu370Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.78

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

MSH6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 2-47799092-T-C is Pathogenic according to our data. Variant chr2-47799092-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799092-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1109T>C	p.Leu370Ser	missense_variant	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.1109T>C	p.Leu370Ser	missense_variant	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2020	The p.Leu370Ser variant in MSH6 has been identified in at least 14 individuals with Lynch syndrome associated cancers and segregated with disease in 4 affected relatives from 2 families (Egoavil 2013, Batte 2014, Pearlman 2017, GeneDx pers. comm., Ambry pers. comm.). In addition, tumors sampled from at least 10 individuals lacked MSH6 expression and/or showed high microsatellite instability, while at least one tumor showed normal MSH6 expression and/or low microsatellite instability. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID #89172) and was absent from large population studies. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4, PM2, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	May 17, 2016	Co-segregation likelihood ratio >250, shared with 3th cousin with loss of MSH6 and others with Lynch cancers in large pedigree, likelihood ration for cosegregation >250 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Dec 10, 2020	The c.1109T>C (p.Leu370Ser) variant in the MSH6 gene is located on the exon 4 and is predicted to replace leucine with serine at codon 370 (p.Leu370Ser). The variant has been reported in multiple individuals with Lynch syndrome-associated cancers (PMID: 32652087, 34994648, 30019097, 24933100, 24244552) and segregating with hereditary cancer syndrome in a family (PMID: 27978560). The variant is reported in ClinVar (ID: 89172). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.811). Therefore, the c.1109T>C (p.Leu370Ser) variant in the MSH6 gene has been classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 07, 2024	This missense variant replaces leucine with serine at codon 370 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 observed in individuals affected with Lynch syndrome (PMID: 32652087, 33393477), with endometrial cancer and/or colorectal cancer (PMID: 24933100, 24244552, 28765196, 30019097), or unspecified cancers (PMID: 28765196). Moreover, it has been observed to segregate with Lynch syndrome related cancers in one family (PMID: 27978560). In addition, a multifactorial likelihood model using in silico data have suggested this variant have a high probability of being deleterious (PMID: 23621914). 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. -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2025	Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 24244552, 24933100, 27978560, 30019097, 32652087, 33393477); 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; This variant is associated with the following publications: (PMID: 24933100, 26333163, 23621914, 27978560, 30019097, 30695780, 32652087, 32719484, 35366121, 31391288, 17531815, 21120944, 24244552, 33393477, 36243179, 37030500, 37751191, 37833309, 37751715, 34994648) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 11, 2022	PP3, PP4, PM2, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2024	The MSH6 c.1109T>C (p.Leu370Ser) variant has been reported in the published literature in multiple individuals affected with Lynch syndrome including colorectal cancer and endometrial cancer (PMIDs: 37751191 (2024), 37833309 (2023), 34994648 (2021), 33393477 (2021), 31391288 (2020), 32652087 (2020), 30019097 (2019), 27978560 (2016), 24933100 (2014), 24244552 (2013)). It was identified in molecular studies examining mismatch repair protein-deficient non-neoplastic colonic crypts and endometrial glands that were associated with underlying Lynch syndrome (PMID: 37030500 (2023)). Co-segregation of the variant with Lynch syndrome was observed in a large family (PMID: 37751715 (2023)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 2023	The p.L370S pathogenic mutation (also known as c.1109T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1109. The leucine at codon 370 is replaced by serine, an amino acid with dissimilar properties. This variant has been found to co-segregate with disease in HNPCC/Lynch syndrome families (Ambry internal data; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This variant was detected in 1/173 unselected Spanish women with endometrial cancer; tumor studies for this individual showed microsatellite stability (MSS) with loss of MSH6 protein expression, but intact MSH2 protein expression (Egoavil C et al. PLoS One. 2013 Nov 7;8(11):e79737). This alteration was also detected in a 53-year-old woman whose endometrial cancer showed low microsatellite instability (MSI-L) with normal protein expression for all the mismatch repair proteins; family history was noncontributory (Batte BA et al. Gynecol Oncol. 2014 Aug;134(2):319-25). In addition, this variant has been identified in numerous individuals whose HNPCC/Lynch syndrome-associated tumors demonstrated isolated loss of MSH6 staining on immunohistochemistry and/or had family histories that met Amsterdam II criteria (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2022	This missense variant replaces leucine with serine at codon 370 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 observed in individuals affected with Lynch syndrome (PMID: 32652087, 33393477), with endometrial cancer and/or colorectal cancer (PMID: 24933100, 24244552, 28765196, 30019097), or unspecified cancers (PMID: 28765196). Moreover, it has been observed to segregate with Lynch syndrome related cancers in one family (PMID: 27978560). In addition, a multifactorial likelihood model using in silico data have suggested this variant have a high probability of being deleterious (PMID: 23621914). 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. -

Lynch syndrome 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 11, 2023

This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 30, 2021

Variant summary: MSH6 c.1109T>C (p.Leu370Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250994 control chromosomes (gnomAD). c.1109T>C has been reported in the literature in multiple individuals affected with Lynch Syndrome and endometrial cancer (example, Egoavil_2013, Pearlman_2017, Chen_2020, Li_2020, Hampel_2021). Most of the reported patients were noted with loss of MSH6 expression in tumors by IHC analysis, although one patient was reported with intact MSH6 (Chen_2020). Furthermore, one of these studies reported co-segregation of the variant with disease among two first and second generation relatives within the family (Pearlman_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and as likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic. -

MSH6-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2024

The MSH6 c.1109T>C variant is predicted to result in the amino acid substitution p.Leu370Ser. This variant has been reported in individuals with colorectal cancer (Pearlman et al. 2017. PubMed ID: 27978560) and endometrial cancer (Egoavil et al. 2013. PubMed ID: 24244552; Batte et al. 2014. PubMed ID: 24933100). At least one tumor showed microsatellite instability and/or abnormal immunohistochemistry (Pearlman et al. 2017. PubMed ID: 27978560). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89172/?new_evidence=true). This variant is interpreted as likely pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 370 of the MSH6 protein (p.Leu370Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with endometrial cancer and/or colorectal cancer (PMID: 24244552, 24933100, 27978560; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89172). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;D;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.3	.;.;M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.3	.;D;D;.;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	.;D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.98	.;.;D;.;.
Vest4		0.65
MVP		0.99
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.75
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587779204; hg19: chr2-48026231;