2-47471006-C-T

Variant names:

• chr2-47471006-C-T
• rs1285862035
• NM_000251.3:c.1703C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000251.3(MSH2):​c.1703C>T​(p.Thr568Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T568R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.46
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.208401).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1703C>T	p.Thr568Ile	missense_variant	Exon 11 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1703C>T	p.Thr568Ile	missense_variant	Exon 11 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426566 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 712032

African (AFR) AF: 0.00 AC: 0 AN: 32814

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 85324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080466

Other (OTH) AF: 0.00 AC: 0 AN: 59100

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MSH2-related disorder Uncertain:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.1703C>T variant is predicted to result in the amino acid substitution p.Thr568Ile. To our knowledge, this variant has not been reported in individuals with the MSH2-related disorders in the literature or in a large population database, indicating this variant is rare. A cell-based functional study via massively parallel screening suggested that this variant may result in loss of function (Table S5, Jia et al. 2021. PubMed ID: 33357406; Table 1, Scott et al. 2022. PubMed ID: 36550560). This variant is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/479822/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 568 of the MSH2 protein (p.Thr568Ile). 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: 479822). Invitae Evidence Modeling incorporating data from in vitro 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T568I variant (also known as c.1703C>T), located in coding exon 11 of the MSH2 gene, results from a C to T substitution at nucleotide position 1703. The threonine at codon 568 is replaced by isoleucine, an amino acid with similar properties. 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 Jan;108:163-175). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.010
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.20	N;.;.;.
PhyloP100		3.5
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	N;N;.;N
REVEL	Uncertain	0.51
Sift	Benign	0.083	T;T;.;T
Sift4G	Benign	0.070	T;T;.;T
Polyphen		0.0010	B;.;.;B
Vest4		0.45
MutPred		0.49		Loss of phosphorylation at T568 (P = 0.0313);.;Loss of phosphorylation at T568 (P = 0.0313);Loss of phosphorylation at T568 (P = 0.0313);
MVP		0.92
MPC		0.0076
ClinPred		0.34	T
GERP RS		3.6
Varity_R		0.12
gMVP		0.32
Mutation Taster		=42/58	disease causing

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: rs1285862035; hg19: chr2-47698145;