rs587779136

chr2-47476457-C-Gchr2-47476457-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):c.2096C>G(p.Ser699Ter) 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. S699S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 2.00

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 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 2-47476457-C-G is Pathogenic according to our data. Variant chr2-47476457-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 90885.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476457-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2096C>G	p.Ser699Ter	stop_gained	13/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2096C>G	p.Ser699Ter	stop_gained	13/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2014	This pathogenic variant is denoted MSH2 c.2096C>G at the cDNA level and p.Ser699Ter (S699X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 17, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 16, 2017	- -

Lynch syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 07, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation introducing premature termination codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

This sequence change creates a premature translational stop signal (p.Ser699*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 90885). 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

Jun 08, 2018

The p.S699* pathogenic mutation (also known as c.2096C>G), located in coding exon 13 of the MSH2 gene, results from a C to G substitution at nucleotide position 2096. This changes the amino acid from a serine to a stop codon within coding exon 13. This mutation has been identified in a patient with early onset colorectal cancer and a family history of Lynch syndrome-related cancers (Pearlman R et al. JAMA Oncol. 2017 Apr 1;3:464-471). 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	0.30
Cadd	Pathogenic	39
Dann	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.62	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.91
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs587779136; hg19: chr2-47703596;