chr2-47476513-C-T

Position:

• chr2-47476513-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.2152C>T​(p.Gln718Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q718Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:12 O:1
• Conservation: PhyloP100: 5.72

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 2-47476513-C-T is Pathogenic according to our data. Variant chr2-47476513-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90909.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476513-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2152C>T	p.Gln718Ter	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	c.2152C>T	p.Gln718Ter	stop_gained	13/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 08, 2021	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate -

Lynch syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation introducing premature termination codon -
Pathogenic, criteria provided, single submitter	research	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	Jan 30, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2021	The p.Q718* pathogenic mutation (also known as c.2152C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2152. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This mutation has been identified in multiple hereditary non-polyposis colorectal cancer (HNPCC)//Lynch syndrome families to date, most of them of Portuguese descent (Isidro G et al. Hum. Mutat., 2000 Jan;15:116; Lage PA et al. Cancer, 2004 Jul;101:172-7; Ewald J et al. Br J Surg, 2007 Aug;94:1020-7; Valentin MD et al. Fam. Cancer, 2011 Dec;10:641-7; Monteiro Santos EM et al. BMC Cancer, 2012 Feb;12:64; Rossi BM et al. BMC Cancer. 2017 Sep;17(1):623; Schneider NM et al. Cancer Med. 2018 May;7(5):2078-88). It has also been reported in three families with early-onset and/or familial prostate cancer, along with other more typical Lynch-associated tumors (Maia S et al. Fam. Cancer, 2016 Jan;15:111-21). Of note, this alteration is designated as p.Gln718* and p.Gln718Ter in published literature. 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	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. This variant has not been identified 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. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Gln718X variant has been previously reported in the literature in 10 of 416 proband chromosomes in individuals meeting various criteria for Lynch syndrome or early onset colorectal cancer (Ewald 2007, Isido 1999, Lage 2004, Terdiman 2002, Santos 2012) and an MSH2 deficient tumour was demonstrated by IHC for this variant in at least one study (Ewald 2007). The variant was also identified by the MMRV (memorial university database), and the InSight colorectal cancer database. The p.Gln718X variant leads to a premature stop codon at position 718, which is predicted to lead to a truncated or absent protein and loss of function. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease for Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 08, 2024

Variant summary: MSH2 c.2152C>T (p.Gln718X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251584 control chromosomes (gnomAD). c.2152C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Isidro_1999, Bonadona_2011, Valentin_2011, Monteiro Santos_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15222003, 21681552, 21642682, 24344984, 10612836, 22321913). ClinVar contains an entry for this variant (Variation ID: 90909). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 12, 2016

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change creates a premature translational stop signal (p.Gln718*) 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 premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10612836, 11910346, 15222003, 21681552, 26289772, 26437257). ClinVar contains an entry for this variant (Variation ID: 90909). For these reasons, this variant has been 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	49
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.98
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs587779139; hg19: chr2-47703652; COSMIC: COSV99254705;