2-47410215-T-C

Variant names:

• chr2-47410215-T-C
• rs63750214
• NM_000251.3:c.488T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP6

The NM_000251.3(MSH2):​c.488T>C​(p.Val163Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V163G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.96
• Publications: 16 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 30 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 chr2-47410215-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 91108.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP6: Variant 2-47410215-T-C is Benign according to our data. Variant chr2-47410215-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229726.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.488T>C	p.Val163Ala	missense_variant	Exon 3 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.488T>C	p.Val163Ala	missense_variant	Exon 3 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Jun 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with alanine at codon 163 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). In a colorectal cancer case-control study, this variant has been reported in 1/12503 cases & 0/23705 controls (PMID: 33309985). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.488T>G (p.Val163Gly) and c.488T>A (p.Val163Asp), are considered to be disease-causing (ClinVar variation ID: 91108, 91107), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aug 24, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Lynch syndrome Uncertain:1

Feb 24, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with alanine at codon 163 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.488T>G (p.Val163Gly), is considered to be disease-causing (ClinVar variation ID: 91108), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jan 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 163 of the MSH2 protein (p.Val163Ala). 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. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 33357406). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 229726). This missense change has been observed in individual(s) with colorectal cancer (PMID: 33309985). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D;.;.;.
Eigen	Benign	0.0024
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Uncertain	0.010	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;N;D;.;D
REVEL	Pathogenic	0.67
Sift	Benign	0.085	T;T;T;.;T
Sift4G	Benign	0.23	T;T;T;.;T
Polyphen		0.053	B;.;.;.;B
Vest4		0.70
MutPred		0.68		Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.92
MPC		0.0069
ClinPred		0.94	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.73
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs63750214; hg19: chr2-47637354;