2-47403192-A-T

Position:

• chr2-47403192-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001406654.1(MSH2):​c.-340A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,244 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 Uncertain significance (★★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: MSH2 NM_001406654.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 7.84

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1A>T	p.Met1?	initiator_codon_variant	1/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1A>T	p.Met1?	initiator_codon_variant	1/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000197 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Insufficient evidence -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2022

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. 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. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90834). Disruption of the initiator codon has been observed on the opposite chromosome (in trans) from a pathogenic variant in MSH2 in an individual who was not affected with recessive MSH2-related conditions (PMID: 18781192, 25639900). This suggests that this variant may not be disease-causing. Disruption of the initiator codon has been observed in individual(s) with MSH2-related conditions (PMID: 9718327, 18033691, 23047549, 28944238). This variant is present in population databases (rs267607911, gnomAD 0.007%). This sequence change affects the initiator methionine of the MSH2 mRNA. The next in-frame methionine is located at codon 26. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2024

The p.M1? variant (also known as c.1A>T) is located in coding exon 1 of the MSH2 gene and results from a A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). Alterations at the initiation codon of MSH2 have been identified in several cancer cohorts including ovarian cancer, early-onset colorectal cancer (diagnosed under age 30) and known or suspected Lynch syndrome cases; however, tumors do not consistently demonstrate a pattern of MSI and mismatch repair protein-deficient IHC staining (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep 63(3):749-59; Otway R et al. Hum. Mutat. 2000;16(1):61-7; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354(26):2751-63; Barnetson RA et al. Hum. Mutat. 2008 Mar;29(3):367-74; Pal T et al. Br. J. Cancer. 2012 Nov;107(10):1783-90; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). Further, transfection of a similar alteration impacting the initiation codon of MSH2, c.1A>C, cDNA into an MSH2-null, human endometrial cancer cell line showed slight, but statistically significant decrease in repair of an exogenous mismatched protein. This attenuated effect may be due to partial function of the truncated protein and/or expression of the full-length protein resulting from weak translation at the altered, non-AUG start codon, which was detected concomitantly with the truncated protein in this study (Cyr JL et al. Mol. Carcinog. 2012 Aug;51(8):647-58). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.68	D
PROVEAN	Benign	-1.4	N;.;N
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		0.52	P;.;P
Vest4		0.96
MutPred		1.0		Loss of methylation at K6 (P = 0.071);Loss of methylation at K6 (P = 0.071);Loss of methylation at K6 (P = 0.071);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.52

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: rs267607911; hg19: chr2-47630331;