2-47408506-G-C

Variant names:

• chr2-47408506-G-C
• rs41295286
• NM_000251.3:c.317G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000251.3(MSH2):​c.317G>C​(p.Arg106Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R106K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.669
• Publications: 14 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_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15087852).
• BP6: Variant 2-47408506-G-C is Benign according to our data. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749. Variant chr2-47408506-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 483749.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.317G>C	p.Arg106Thr	missense_variant	Exon 2 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.317G>C	p.Arg106Thr	missense_variant	Exon 2 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459848 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726340

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110280

Other (OTH) AF: 0.00 AC: 0 AN: 60336

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

Oct 06, 2023

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. -

Sep 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with threonine at codon 106 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). 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. -

Lynch syndrome Uncertain:1

Oct 06, 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 arginine with threonine at codon 106 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). 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

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 106 of the MSH2 protein (p.Arg106Thr). 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: 483749). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Benign	0.24
DEOGEN2	Benign	0.42	T;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.59	N;.;.;.;.
PhyloP100		0.67
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N;N;N;.;N
REVEL	Uncertain	0.53
Sift	Benign	0.28	T;D;T;.;T
Sift4G	Benign	0.49	T;D;T;.;T
Polyphen		0.012	B;.;.;.;B
Vest4		0.41
MutPred		0.56		Loss of MoRF binding (P = 0.0043);.;.;Loss of MoRF binding (P = 0.0043);Loss of MoRF binding (P = 0.0043);
MVP		0.94
MPC		0.0062
ClinPred		0.41	T
GERP RS		-1.8
Varity_R		0.14
gMVP		0.38
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41295286; hg19: chr2-47635645; COSMIC: COSV51883407;