2-47482797-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000251.3(MSH2):c.2653C>T(p.Gln885Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q885Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 1.91

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47482797-C-T is Pathogenic according to our data. Variant chr2-47482797-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 91033.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47482797-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2653C>T	p.Gln885Ter	stop_gained	16/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2653C>T	p.Gln885Ter	stop_gained	16/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:3

Pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 13, 2018	This variant is before the cutoff (codon 888) and therefore Class 5 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 09, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 16, 2021	- -

not provided Pathogenic:3

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	Nov 03, 2022	This nonsense variant causes the premature termination of MSH2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in families with a history of Lynch Syndrome (PMID: 14635101 (2003), PMID: 12658575 (2003)) and in an individual screened for Lynch Syndrome (PMID: 31615790 (2020)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	This variant is denoted MSH2 c.2653C>T at the cDNA level and p.Gln885Ter (Q885X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG). This variant has been reported in several individuals with colon cancer and in one with ovarian cancer (Taylor 2003, Wagner 2003, Evans 2009, Schofield 2012, Hampel 2018). Due to the position of the variant, nonsense mediated decay is not expected to occur, but it might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene contains the helix-turn-helix domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). Additionally, Wielders et al. (2017) found that MSH2 variants lacking the c-terminus severely destabilize MSH2/MSH6 interaction and result in increased microsatellite instability. MSH2 Gln885Ter was not observed in large population cohorts (Lek 2016). Based on currently available evidence, we consider this variant to be pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 03, 2023

Variant summary: MSH2 c.2653C>T (p.Gln885X) results in a premature termination codon, predicted to cause a truncation of the helix-turn-helix domain of the encoded protein (Kansikas_2011), though this truncation is not expected to result in nonsense-mediated decay. Truncations downstream of this position have been classified as pathogenic by ClinVar submitters. The variant was absent in 251034 control chromosomes. c.2653C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Wagner_2003, Taylor_2003, Schofield_2012, Hampel_2018, Wischhusen_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel, have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln885*) in the MSH2 gene. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12658575, 14635101). ClinVar contains an entry for this variant (Variation ID: 91033). Studies have shown that this variant results in skipping of exon 16 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu888Cysfs*4) have been determined to be pathogenic (PMID: 9222765, 9774676, 17531815, 18822302; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2022

The p.Q885* pathogenic mutation (also known as c.2653C>T), located in coding exon 16 of the MSH2 gene, results from a C to T substitution at nucleotide position 2653. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This mutation has been described in an HNPCC family meeting Amsterdam criteria (Wagner A et al. Am J Hum Genet. 2003 May;72(5):1088-100). This alteration has also been reported in at least one individual from a cohort of 215 UK patients referred for genetic testing on the basis of a family history consistent with HNPCC (Taylor CF et al. Hum. Mutat., 2003 Dec;22:428-33). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.93
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -18

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

Publications

LitVar

Other links and lift over

dbSNP: rs63750808; hg19: chr2-47709936;