2-47414405-T-G

Variant names:

• chr2-47414405-T-G
• rs63750640
• NM_000251.3:c.929T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PP3_Moderate PP1_Strong PM5 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000251.3(MSH2):c.929T>G (p.Leu310Arg) variant is a missense variant replacing Leucin 310 to Arginin. The variant has been reported to co-segregate with disease in pedigree(s) with a combined* Bayes Likelihood Ratio >18.72 in ≥2 families (PMID:30376427, 33848333) (PP1_STR).The variant is a missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity >0.81 as per http://priors.hci.utah.edu/PRIORS (PP3_MOD).The variant is a missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level; p.Leu310Pro classified as Class 5 by InSiGHT (PM5).The variant has been detected in at least 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markersg and/or loss of MMR protein expression consistent with the variant location (PP4_MOD).The variant is not reported in gnomAD v4.1 (PM2_SUP). In summary, this variant meets the criteria to be classified as pathogenic for autosomal-dominant inherited Lynch-syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PM5, PP1_strong, PP4_moderate, PP3_moderate and PM2_supporting applied. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA022554/MONDO:0007356/137

• Frequency: Genomes: not found (cov: 26)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.97
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.929T>G	p.Leu310Arg	missense_variant	Exon 5 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.929T>G	p.Leu310Arg	missense_variant	Exon 5 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome Pathogenic:1

Apr 03, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The MSH2 variant designated as NM_000251.2:c.929T>G (p.L310R) is classified as pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303). This allele had a likelihood ratio of 19.6 to 1 (Thompson, et al., 2003, PMID:2900794) indicating that this allele is likely to explain the Lynch syndrome associated cancers in this family (e.g. colon cancer, gastric cancer, ovarian cancer, endometrial cancer, and sebaceous adenoma). The genomic position is highly conserved. The variant is predicted to be probably damaging by analysis with computerized tools PolyPhen 2 and SIFT and has a MAPP score of 33.02. By consensus, prior probability of pathogenicity based on in-silico scores are capped at a maximum of 90%. In Bayesian analysis, the likelihood ratio from our study, 19.6 to 1, was combined with the 90% prior probability to give a 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This finding is also consistent with other supporting data. This variant was identified in two family members whose colon tumors had loss of MSH2 and MSH6. It has also been reported by the InSIGHT consortium database in one patient whose tumor had loss of MSH2 and MSH6. A different variant at the same amino acid position is known to be deleterious (Chao 2008, PMID:18383312). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (Ali et al, 2012, PMID:22290698). The variant is not listed in population databases such as ExAC or gnomAD. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives >99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is expected to alter MSH2 function and modify cancer risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with Lynch syndrome associated cancers (PMID: 30374176). It has also been observed to segregate with disease in related individuals. This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 310 of the MSH2 protein (p.Leu310Arg). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 91246). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is expected to disrupt MSH2 function. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 25, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L310R pathogenic mutation (also known as c.929T>G), located in coding exon 5 of the MSH2 gene, results from a T to G substitution at nucleotide position 929. The leucine at codon 310 is replaced by arginine, an amino acid with dissimilar properties. This mutation was found to segregate with disease in one family meeting Amsterdam criteria, including two affected carriers whose tumors demonstrated loss of MSH2 and MSH6 protein expression by immunohistochemistry analysis (IHC) (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This alteration has been reported in two additional individuals diagnosed with MSI-H colon cancer with absent MSH2 staining on IHC, one of whom was diagnosed at age 45 or younger (Perea J et al. Ann. Surg. Oncol., 2011 Nov;18:3285-91; Latham A et al. J Clin Oncol, 2019 02;37:286-295). 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 deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;.;.;.
PhyloP100		6.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D;D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MVP		0.99
MPC		0.030
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750640; hg19: chr2-47641544; COSMIC: COSV51879724;