rs63750828

Variant names:

• chr2-47416351-G-A
• rs63750828
• NM_000251.3:c.998G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47416351-G-A
• chr2-47416351-G-T
• chr2-47416351-G-C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.998G>A​(p.Cys333Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000211169: Published functional studies demonstrate a damaging effect: increased protein turnover with reduced steady-state protein levels, loss of interaction with the MSH3 protein, and decreased MMR efficiency (Ollila et al., 2006" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C333F) has been classified as Likely pathogenic. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 9.81
• Publications: 25 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: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000211169: Published functional studies demonstrate a damaging effect: increased protein turnover with reduced steady-state protein levels, loss of interaction with the MSH3 protein, and decreased MMR efficiency (Ollila et al., 2006; Gammie et al., 2007; Arlow et al., 2013; Houlleberghs et al., 2016); SCV000592484: Functional characterization of MSH2 missense variant p.Cys333Tyr showed loss of interaction with all partners (Gammie 2007).; SCV000275379: "In vitro functional studies showed normal MSH6 interaction but reduced mismatch repair efficiency compared to the wild-type (7.0% versus 44.7%) and decreased protein stability (Ollila S et al. Gastroenterology. 2006 Nov;131(5):1408-17; Nielsen S et al. PLoS Genet. 2017 04;13(4):e1006739). Additional functional studies have shown p.C333Y to result in loss of mismatch repair activity, decreased MSH2 levels (1% of wild type) and loss of subunit interaction (Gammie AE et al. Genetics. 2007 Oct;177(2):707-21). This alteration was also found to be pathogenic by a functional screening method utilizing oligo targeting mutagenesis and analysis of cell colonies resistant to methylation (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113(15):4128-33)."; SCV000685148: Functional studies have shown that this variant disrupts MSH2 protein function, decreasing protein stability and expression and resulting in defective mismatch repair (PMID: 17101317, 17720936, 18951462, 23248292, 26951660, 28422960, 33357406).; SCV000751109: Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 17720936, 18951462, 26951660).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 33 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 chr2-47416351-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 638846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 2-47416351-G-A is Pathogenic according to our data. Variant chr2-47416351-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 91273.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.998G>A	p.Cys333Tyr	missense	Exon 6 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.998G>A	p.Cys333Tyr	missense	Exon 6 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.998G>A	p.Cys333Tyr	missense	Exon 6 of 18	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.998G>A	p.Cys333Tyr	missense	Exon 6 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.998G>A	p.Cys333Tyr	missense	Exon 6 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1049G>A	p.Cys350Tyr	missense	Exon 7 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000590 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Lynch syndrome 1 (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	-	Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.96
MPC		0.027
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.80
Mutation Taster		=1/99	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: rs63750828; hg19: chr2-47643490; COSMIC: COSV51881721;