Variant 2-47416429-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000251.3(MSH2):c.1076G>C(p.Arg359Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R359S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.81

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47429742-A-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 2-47416429-G-C is Pathogenic according to our data. Variant chr2-47416429-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.1076G>C	p.Arg359Thr	missense_variant, splice_region_variant	6/16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.1076G>C	p.Arg359Thr	missense_variant, splice_region_variant	6/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726442

show subpopulations

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lynch syndrome 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 31, 2023	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 30, 2022	- -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 05, 2024

Variant summary: MSH2 c.1076G>C (p.Arg359Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' donor site and one predicts the variant abolishes this site. However, these predictions have yet to be confirmed by published functional studies. The variant was absent in 251388 control chromosomes (gnomAD). c.1076G>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Espenschied_2017, Dong_2020). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1077A>T, p.Arg359Ser), supporting the critical relevance of codon 359 to MSH2 protein function. At least one publication reports experimental evidence evaluating an impact on protein function in a massively parallel screen of missense varaints in human cells, finding that the variant results in a deleterious effect (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 32030746, 28514183, 33357406). ClinVar contains an entry for this variant (Variation ID: 142767). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch-like syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 05, 2024

The MSH2 c.1076G>C (p.Arg359Thr) variant has been reported in the published literature in a functional study showing this variant results in abnormal protein function (PMID: 33357406 (2021)). This variant has also been found in an individual affected with a sebaceous carcinoma and uterine cancer with a family history of Lynch-syndrome associated cancers (Quest internal data), as well as an individual that meets Amsterdam I criteria for Lynch syndrome (Ambry Genetics, ClinVar ID: 142767). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 359 of the MSH2 protein (p.Arg359Thr). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 28514183; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142767). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MSH2 function (PMID: 33357406). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the p.Arg359 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11870161, 17165155, 17720936, 18781619). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Nov 08, 2021

The c.1076G>C pathogenic mutation (also known as p.R359T), located in coding exon 6 of the MSH2 gene, results from a G to C substitution at nucleotide position 1076. The amino acid change results in arginine to threonine at codon 359, an amino acid with similar properties. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability or loss of MSH2 expression by immunohistochemistry, identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. Although, this change occurs in the last base pair of coding exon 6, in silico splice site analysis predicts that this alteration will not have any significant effect on splicing and RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.94

D;.;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.9

D;D;.;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0

D;D;.;D

Polyphen

0.97

D;.;.;D

Vest4

0.95

MutPred

0.95

Gain of phosphorylation at R359 (P = 0.0899);.;Gain of phosphorylation at R359 (P = 0.0899);Gain of phosphorylation at R359 (P = 0.0899);

MVP

0.99

MPC

0.026

ClinPred

1.0

GERP RS

5.6

Varity_R

0.96

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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