2-47445632-T-G

Variant names:

• chr2-47445632-T-G
• rs1060502025
• NM_000251.3:c.1361T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000251.3(MSH2):​c.1361T>G​(p.Ile454Arg) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I454T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 5.79
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 37 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47445632-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1770848.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 2-47445632-T-G is Pathogenic according to our data. Variant chr2-47445632-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 495768.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1361T>G	p.Ile454Arg	missense_variant	Exon 8 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1361T>G	p.Ile454Arg	missense_variant	Exon 8 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Aug 01, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 33357406]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 26, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I454R variant (also known as c.1361T>G), located in coding exon 8 of the MSH2 gene, results from a T to G substitution at nucleotide position 1361. The isoleucine at codon 454 is replaced by arginine, an amino acid with similar properties. One study reported this alteration in two unrelated individuals, one with endometrial and ovarian cancer diagnosed at age 42 whose family history met Amsterdam criteria and one with colorectal cancer diagnosed at age 39 who met Bethesda guidelines. The endometrial and colorectal tumors of these individuals showed high microsatellite instability (MSI-H) with absent MSH2 and MSH6 staining on immunohistochemistry (IHC). The individual with colorectal cancer was also positive for an MSH6 alteration. Furthermore, using family history, pathology, genetic information and supporting evidence from eight different in silico tools at the RNA and protein level, the investigators in this study classified p.I454R as probably damaging (Borras E et al. Cancer Prev. Res. (Phila) 2017 Oct;10(10):580-587). This alteration was also identified in another individual with a MSI-H rectal tumor that displayed loss of both MSH2/MSH6 on IHC and whose family history met Amsterdam II criteria for Lynch syndrome (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 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. -

not provided Uncertain:1

Jul 06, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MSH2 c.1361T>G (p.Ile454Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 119816 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jul 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 454 of the MSH2 protein (p.Ile454Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 495768). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.8	D;D;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.88
MutPred		0.77		Gain of disorder (P = 0.0054);.;Gain of disorder (P = 0.0054);Gain of disorder (P = 0.0054);
MVP		0.96
MPC		0.0060
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.84
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060502025; hg19: chr2-47672771;