Variant 2-47476399-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-47476399-C-T is Pathogenic according to our data. Variant chr2-47476399-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 36572.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476399-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2038C>T	p.Arg680Ter	stop_gained	13/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.2038C>T	p.Arg680Ter	stop_gained	13/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251446

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135902

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

2

AN:

1461874

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

727236

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

32

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

1

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:7Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 03, 2020	This nonsense variant causes the premature termination of MSH2 protein synthesis. The frequency of this variant in the general population, 0.0000088 (1/113738 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 20215533 (2010), 21598002 (2011), 23047549 (2012)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2017	The MSH2 c.2038C>T, p.Arg680Ter variant (rs63749932) is a recurrent alteration in families with Lynch syndrome (Brieger 2011, Wijnen 1997, InSiGHT LOVD database). It is listed as pathogenic in ClinVar (Variation ID: 36572) by the International Society for Gastrointestinal Hereditary Tumours (Thompson 2014), and observed once in the Genome Aggregation Database general population database (1/246216 alleles). The variant introduces a premature termination codon, and predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References InSiGHT LOVD database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php?action=search_unique Brieger A et al. Malignant fibrous histiocytoma is a rare Lynch syndrome-associated tumor in two German families. Fam Cancer. 2011; 10(3):591-5. Thompson B et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 2014; 46(2):107-15. Wijnen J et al. Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. Am J Hum Genet. 1997; 61(2):329-35. -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MSH2: PVS1, PM2, PS4:Moderate, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	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: 20215533, 12547705, 15713769, 25648859, 20587412, 24344984, 32549215, 31830689, 29922827, 28888541, 34761457, 31615790, 9311737, 21598002, 23047549, 12414824, 16807412, 18809606, 9718327, 11524701, 11854906, 11208710, 27318266, 18270343, 27013479, 16616355, 15345113, 15849733, 20233461, 19723918, 17312306, 15926618, 12658575, 12112654, 18566915, 27601186, 25980754, 25430799, 26681312, 28176205, 28944238, 29489754, 28874130, 30521064, 30322717, 31939059, 29625052, 31447099, 34178123, 30217226, 32719484, 30787465, 30998989) -

Lynch syndrome 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 31, 2024	This sequence change creates a premature translational stop signal (p.Arg680*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is present in population databases (rs63749932, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20215533, 12547705, 15713769, 25648859, 20587412, 24344984, 32549215, 31830689, 29922827, 28888541, 34761457, 31615790, 9311737, 21598002, 23047549, 12414824, 16807412, 18809606, 9718327, 11524701, 11854906, 11208710, 27318266, 18270343, 27013479, 16616355, 15345113, 15849733, 20233461, 19723918, 17312306, 15926618, 12658575, 12112654, 18566915, 27601186, 25980754, 25430799, 26681312, 28176205, 28944238, 29489754, 28874130, 30521064, 30322717, 31939059, 29625052, 31447099, 34178123, 30217226, 32719484, 30787465, 30998989) . ClinVar contains an entry for this variant (Variation ID: 36572). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 24, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Lynch syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2017	The p.Arg680X variant in MSH2 has been reported in at least 5 individuals with L ynch syndrome-associated cancers (Hendriks 2003, Walsh 2010, Sjursen 2010, Pal 2 012, Dominguez-Valentin 2016). In addition, tumors sampled from 3 individuals sh owed microsatellite instability and lacked MSH2 and MSH6 expression. This varian t has also been identified in 1/66702 of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs63749932). This nonsense variant leads to a premature termination codon at position 680, which is predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the MSH2 gene is an established disease mechanism in individuals with Ly nch Syndrome. Furthermore, the p.Arg680X variant has been classified as pathogen ic on by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107394.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch S yndrome in an autosomal dominant manner based upon the predicted impact to the p rotein. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation introducing premature termination codon -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 11, 2023	This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with Lynch syndrome and/or Lynch syndrome-associated disease (PMID: 12547705, 20587412, 21879275, 23047549, 24344984, 25430799, 27013479, 27601186), as well as in individuals affected with breast cancer or prostate cancer whose tumors displayed abnormal MSH2/MSH6 protein via immunohistochemistry (PMID: 19723918, 20215533). This variant has been identified in 1/251446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 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	Mar 09, 2022	The p.R680* pathogenic mutation (also known as c.2038C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2038. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been identified in multiple individuals/families with HNPCC/Lynch syndrome (Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Levi Z et al. Am. J. Transplant. 2007 Feb;7:476-9; Brieger A et al. Fam. Cancer. 2011 Sep;10:591-5; Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90; Goldberg Y et al. Clin. Genet. 2015 Jun;87:549-53; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; DeRycke MS et al. Mol. Genet. Genomic Med. 2017 Jul;5:553-569; Rossi BM et al. BMC Cancer. 2017 Sep;17:623). 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. -

Lynch-like syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Malignant tumor of ascending colon

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

3DMed Clinical Laboratory Inc

Jan 04, 2018

- -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Arg680*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is present in population databases (rs63749932, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 9311737, 15849733, 18270343, 20215533, 20233461, 20587412, 21598002, 23047549). ClinVar contains an entry for this variant (Variation ID: 36572). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Jan 03, 2024

The MSH2 c.2038C>T (p.Arg680Ter) variant has been reported in many individuals affected with Lynch syndrome (√Ålvarez K et al., PMID: 32549215; Goldberg Y et al., PMID: 25430799; Jiang W et al., PMID: 30521064; Lagerstedt-Robinson K et al., PMID: 27601186; Zhang J et al., PMID: 35939113). This variant has been reported in the ClinVar database as a germline pathogenic variant by 16 submitters, including an expert panel. This variant is only observed on 1/251,446 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

D

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

54

DANN

Uncertain

1.0

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

D

MutationTaster

Benign

1.0

A;A;A

Vest4

0.96

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

2-47476399-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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