rs63750924

Positions:

• chr2-47410107-ATC-A

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.387_388delTC​(p.Gln130fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000124 in 1,613,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 3.99

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]

MSH2 (HGNC:):

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 2-47410107-ATC-A is Pathogenic according to our data. Variant chr2-47410107-ATC-A is described in ClinVar as [Pathogenic]. Clinvar id is 91089.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47410107-ATC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.387_388delTC	p.Gln130fs	frameshift_variant	3/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.387_388delTC	p.Gln130fs	frameshift_variant	3/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461404 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726950

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 AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2015	This deletion of 2 nucleotides in MSH2 is denoted c.387_388delTC at the cDNA level and p.Gln130ValfsX2 (Q130VfsX2) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTC[TC]AGTT. The deletion causes a frameshift, which changes a Glutamine to a Valine at codon 130, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.387_388delTC, also known as 129delTC or c.388_389delTC using alternative nomenclature, has been observed in several individuals with personal and/or family histories consistent with Lynch syndrome (Buerstedde 1995, Wagner 2003, Mangold 2005). We consider this variant to be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2021	The MSH2 c.387_388delTC; p.Gln130ValfsTer2variant (rs63750924) is reported in the literature in several individuals affected with hereditary nonpolyposis colorectal cancer (Buerstedde 1995, Carter 2018, Lamberti 2006, Mangold 2005). This variant is also reported in ClinVar (Variation ID: 91089), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References Buerstedde et al. Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes. J Med Genet. 1995 Nov;32(11):909-12. PMID: 8592341. Carter et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol 2018 Dec;151(3):481-488. PMID: 30322717. Lamberti C et al. Frequency of hereditary non-polyposis colorectal cancer among unselected patients with colorectal cancer in Germany. Digestion. 2006;74(1):58-67. PMID: 17095871. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005 Sep 20;116(5):692-702. PMID: 15849733. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 11, 2015	- -

Lynch syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 27, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Lynch-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation resulting in a stop codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91089). This variant is also known as 129delTC or c.388_389delTC. This premature translational stop signal has been observed in individuals with Lynch syndrome (PMID: 8592341, 10375096, 12658575, 15849733, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln130Valfs*2) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2022

The c.387_388delTC pathogenic mutation, located in coding exon 3 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 387 to 388, causing a translational frameshift with a predicted alternate stop codon (p.Q130Vfs*2). One study identified three individuals heterozygous for this mutation in a Swiss HNPCC family: an individual diagnosed with colon cancer at age 57, an individual diagnosed with rectal cancer at age 46 who was also reported to have several adenomas of the colon, and an individual diagnosed with cancers of the nasopharynx and colon at ages 24 and 43, respectively. Furthermore, one untested obligate carrier in the family was reported to have a glioblastoma multiforme consistent with Turcot's syndrome (Buerstedde JM et al. J. Med. Genet. 1995 Nov;32(11):909-12). An additional study identified this mutation in a single individual with demonstrated absence of MSH2 protein on immunohistochemistry and low microsatellite instability on tumor testing (Lamberti C et al. Digestion 2006;74:58-67). This alteration was reported somatically in a sebaceous neoplasm with absent MSH2 and MSH6 protein (Joly MO et al. Hum. Mutat. 2015 Mar;36:292-5). 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 18, 2023

A known pathogenic mutation was detected in the MSH2 gene (c.387_388delTC). This sequence change creates a premature translational stop signal (p.Gln130Valfs*2) 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 individuals with Lynch syndrome (PMID: 8592341, 10375096, 12658575, 15849733, 28514183). This variant is also known as 129delTC or c.388_389delTC. ClinVar contains an entry for this variant (Variation ID: 91089). For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the MSH2 gene are associated with hereditary nonpolyposis colorectal cancer syndrome, also known as Lynch syndrome. -

Computational scores

Source: dbNSFP v4.3

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: rs63750924; hg19: chr2-47637246;