2-47783243-C-T

Position:

chr2-47783243-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000179.3(MSH6):c.10C>T(p.Gln4*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,611,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MSH6
NM_000179.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 2.05

Variant links:

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]

MSH6 links:

MSH6 (HGNC:):

MSH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 153 pathogenic variants in the truncated region.

PP5

Variant 2-47783243-C-T is Pathogenic according to our data. Variant chr2-47783243-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.10C>T	p.Gln4*	stop_gained	1/10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.10C>T	p.Gln4*	stop_gained	1/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000245

AC:

AN:

244570

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133648

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000547

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1459288

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726018

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome 5

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 28, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Lynch syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 28, 2022	The p.Gln4X variant in MSH6 has been reported in >20 individuals with MSH6-associated cancers, and segregated with disease in at least 4 affected individuals from 3 families (Baglietto 2010 PMID: 20028993, Castellsague 2015 PMID: 25318681, Yurgelun 2015 PMID: 25980754, Shirts 2016 PMID: 26845104, Ghazani 2017 PMID: 28125075, Yurgelun 2017 PMID: 28135145, Carter 2018 PMID: 30322717, Tian 2019 PMID: 31054147, Yang 2019 PMID: 31604779, Perez-Valencia 2020 PMID: 32773772) and is believed to be a novel founder mutation in the French Canadian population (Castellsague 2015 PMID: 25318681). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 183723) and has been identified in 0.006% (7/125024) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 4, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch Syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2017	Variant summary: The MSH6 c.10C>T (p.Gln4X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/270892 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant has been reported to cosegregate in 11 French-Canadian families and was determined to be a founder mutation. One individual was homozygous for the variant and consistent with CMMR-D phenotype (Castellsague_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	The c.10C>T variant in the MSH6 gene is located on the exon 1 and introduces a premature translation termination codon (p.Gln4), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer and is a founder variant in French Canadian population and segregating in 2 families (PMID: 25318681, 25980754, 31604779, 28135145). The variant has also been reported in recessive state from an individual with constitutional MMR deficiency (CMMRD) syndrome (PMID: 32773772). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). Other loss-of-function variants located in the same exon (p.Met1Val, p.Pro57fs) have been interpreted as pathogenic (ClinVar ID: 1517490, 229952). This variant has been reported in ClinVar (ID: 183723). This variant is rare (21/1611488 chromosomes) in general population according to gnomAD. Therefore, the c.10C>T (p.Gln4) variant in the MSH6 gene has been classified as pathogenic. -

not provided

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2023	The MSH6 c.10C>T (p.Gln4*) variant causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in as one of the most common pathogenic Lynch Syndrome variants in French Canadian families in Quebec (PMID: 25318681 (2015)). This variant has also been identified in affected individuals with colorectal and lung cancers (PMIDs: 28135145 (2017), 28125075 (2017) and 20028993 (2010)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2022	Reported as a founder variant in the French Canadian population (Castellsagu 2014); Observed in homozygous state in individuals with personal histories suspicious for constitutional mismatch repair deficiency (CMMR-D) syndrome (Castellsague 2014, Perez-Valencia 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 28514183, 29485237, 20028993, 25980754, 25345868, 25318681, 22949379, 26845104, 28152038, 28135145, 28125075, 29750335, 30702970, 31604779, 31054147, 30322717, 32773772, 31980526, 31948886, 30787465, 27535533) -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 17, 2023	This variant changes 1 nucleotide in exon 1 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 10 individuals and families affected with Lynch syndrome (PMID: 20028993, 25318681), and an individual affected with endometrial cancer (PMID: 26845104). This variant has also been reported homozygous in a 10 year-old individual affected with colorectal cancer, which is consistent constitutional mismatch repair deficiency (PMID: 25318681). This variant has been described as a common founder mutation in the French Canadian population of Quebec (PMID: 25318681). This variant has been identified in 7/275906 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 13, 2022	The p.Q4* pathogenic mutation (also known as c.10C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 10. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This mutation has been identified in patients with Lynch syndrome or colorectal/endometrial cancers (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102(3):193-201; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Yurgelun MB et al. J. Clin. Oncol. 2017 Apr 1;35(10):1086-1095), and has been described as a founder mutation in the French Canadian population of Quebec (Castellsagué E et al. Clin. Genet. 2015 Jun:87(6):536-42). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 01, 2021	- -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 19, 2024

- -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 19, 2023

- -

Carcinoma of colon

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH6 p.Gln4* variant was identified in ClinVar (classified as pathogenic by Ambry Genetics, Invitae, GeneDx, and the University of Washington Department of Laboratory Medicine and as likely pathogenic by Mayo Clinic Genetic Testing Laboratories), COSMIC, COGR (classified as pathogenic by a clinical laboratory), and UMD (1x with a causal classification). This variant was identified in the genome Aggregation Database (beta, October 19th 2016) in 5 of 276350 chromosomes (freq. 0.00002). The variant was not found in dbSNP, â€šÃ„ÃºMismatch Repair Genes Variant Databaseâ€šÃ„Ã¹, â€šÃ„ÃºMMR Gene Unclassified Variants Databaseâ€šÃ„Ã¹, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium database. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Gln4* variant is predicted to lead to a premature stop codon at position 4, which is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. A study by Castellsague (2015) suggests the variant is a novel founder mutation in the French Canadian population. The mutation co-segregated with cancer in 15 of 23 carriers and confers a major risk to develop EC (endometrial cancer). All available tumours from carrier individuals showed MSI and IHC loss of MSH6 protein. In addition, the mutation was found in 16 samples in a control population of 6433 newborns in Quebec (~1/400). The variant was also identified by our laboratory in 2 individuals with endometrial and uterine cancer. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

MSH6-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2024

The MSH6 c.10C>T variant is predicted to result in premature protein termination (p.Gln4*). This variant has been reported to be pathogenic for Lynch syndrome (see example: Supplemental Table 1, Yurgelun et al. 2017. PubMed ID: 28135145), and reported as a common Lynch syndrome variant in the French Canadian population of Quebec (Castellsagué et al. 2014. PubMed ID: 25318681). This variant has been identified in individuals with ovarian tumor (Table S1, Carter et al. 2018. PubMed ID: 30322717), prostate cancer (Table S1, Wu et al. 2020. PubMed ID: 31948886), glioblastoma (Yang et al. 2019. PubMed ID: 31604779), endometrial cancer (Table S1, Tian et al. 2019. PubMed ID: 31054147), and in the homozygous state in an individual with constitutional mismatch repair deficiency (Perez-Valencia et al. 2020. PubMed ID: 32773772). This variant is reported in 0.0056% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183723/). Nonsense variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change creates a premature translational stop signal (p.Gln4*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs786201042, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20028993, 25318681). It is commonly reported in individuals of French Canadian ancestry (PMID: 20028993, 25318681). ClinVar contains an entry for this variant (Variation ID: 183723). For these reasons, this variant has been classified as Pathogenic. -

Mismatch repair cancer syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Human Genetics, Medical University Innsbruck

May 06, 2020

- -

Endometrial carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Benign

0.42

Vest4

0.53

GERP RS

4.1

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over