chr2-47475066-C-T

Position:

• chr2-47475066-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.1801C>T​(p.Gln601Ter) variant causes a stop gained change. 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 5.46

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 2-47475066-C-T is Pathogenic according to our data. Variant chr2-47475066-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1758.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475066-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.1801C>T	p.Gln601Ter	stop_gained	12/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1801C>T	p.Gln601Ter	stop_gained	12/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 15, 2024	A heterozygous nonsense variant in exon 12 of the MSH2 gene (chr2:g.47475066C>T; Depth: 111x) that results in a stop codon and premature truncation of the protein at codon 601 (p.Gln601Ter; ENST00000233146.7) was detected. The p.Gln601Ter variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is damaging by Mutation Taster2 tool. The reference codon is conserved in mammals. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 03, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2017	This variant is denoted MSH2 c.1801C>T at the cDNA level and p.Gln601Ter (Q601X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in an individual with early onset colorectal cancer, whose tumor studies demonstrated microsatellite instability (Farrington 1998). Additionally, this variant has been reported in a family with Muir-Torre syndrome and is considered pathogenic (Kolodner 1994). -

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 -

Muir-Torré syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1994

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change creates a premature translational stop signal (p.Gln601*) 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 colorectal cancer (PMID: 7585065, 7713503). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Q600Ter. ClinVar contains an entry for this variant (Variation ID: 1758). 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

Dec 12, 2023

The p.Q601* pathogenic mutation (also known as c.1801C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1801. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has previously been reported in multiple individuals diagnosed with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Kolodner RD et al. Genomics 1994 Dec;24(3):516-26; Liu B et al. Nat. Med. 1995 Apr;1(4):348-52; Farrington SM et al. Am J Hum Genet. 1998;63:749-759; Chubb D et al. Nat Communications. 2016 June;7:11883). 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	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.98
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750047; hg19: chr2-47702205; COSMIC: COSV99254746; COSMIC: COSV99254746;