2-47403219-C-T

Position:

• chr2-47403219-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.28C>T​(p.Gln10*) 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 1.96

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 381 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47403219-C-T is Pathogenic according to our data. Variant chr2-47403219-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 91055.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47403219-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.28C>T	p.Gln10*	stop_gained	1/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.28C>T	p.Gln10*	stop_gained	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448260 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719318

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 05, 2017	The p.Gln10X variant in MSH2 has been reported in 1 individual with MSH2-associa ted cancer (Mangold 2005) and was absent from large population studies. This non sense variant leads to a premature termination codon at position 10, which is pr edicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechanism in Lynch syndrome. In addit ion, this variant was classified as pathogenic on Sept 13, 2013 by the ClinGen-a pproved InSiGHT expert panel (ClinVar SCV000107586.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon absence from controls and its predicted impact on th e protein. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 26, 2023

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 12, 2023

Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 91055). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15849733). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln10*) in the MSH2 gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.59	D
Vest4		0.72
GERP RS		3.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

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: rs63751099; hg19: chr2-47630358;