rs63750280

Variant names:

• chr2-47475129-C-A
• rs63750280
• NM_000251.3:c.1864C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47475129-C-A
• chr2-47475129-C-G
• chr2-47475129-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.1864C>A​(p.Pro622Thr) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P622S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.21
• Publications: 12 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 27 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 chr2-47475129-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3073881.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-47475129-C-A is Pathogenic according to our data. Variant chr2-47475129-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 90805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1864C>A	p.Pro622Thr	missense_variant	Exon 12 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1864C>A	p.Pro622Thr	missense_variant	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Aug 04, 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: 30998989]. -

not provided Pathogenic:1

Mar 06, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MSH2 c.1864C>A at the cDNA level, p.Pro622Thr (P622T) at the protein level, and results in the change of a Proline to a Threonine (CCA>ACA). This variant was observed in at least one individual from with colorectal cancer as well as MSH2-absent bladder and ureter cancers (Skeldon 2013). This variant was also identified in an individual with colon cancer from a family meeting Amsterdam I criteria (Chialina 2006). In addition, a different variant at the same position, Pro622Leu, has been reported in individuals with Lynch syndrome and functional studies have demonstrated impaired function compared to wild type (Mastrocola 2010, Drost 2012, Thompson 2013).MSH2 Pro622Thr was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Pro622Thr occurs at a position that is conserved across species and is located in the ATPase domain and the region of interaction with EXO1 (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH2 Pro622Thr to be a likely pathogenic variant. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jun 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu622 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8261515, 16616355, 17720936, 19267393, 21309037, 22949379, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MSH2 function (PMID: 28422960, 30998989). 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. ClinVar contains an entry for this variant (Variation ID: 90805). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 16426447, 22883484, 25025451, 25117503, 28874130, 29987844). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 622 of the MSH2 protein (p.Pro622Thr). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 13, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P622T variant (also known as c.1864C>A), located in coding exon 12 of the MSH2 gene, results from a C to A substitution at nucleotide position 1864. The proline at codon 622 is replaced by threonine, an amino acid with highly similar properties. This alteration has been reported in two families meeting Amsterdam Criteria (Chialina SG et al. BMC Med. Genet. 2006 Jan 20;7:5; Rosty C et al. Fam. Cancer. 2014 Dec;13(4):573-82). This alteration has also been reported in individuals diagnosed with colon, endometrial and prostate cancers, with tumors showing high microsatellite instability and/or loss of MSH2 and/or MSH6 by IHC (Chialina SG et al. BMC Med. Genet. 2006 Jan 20;7:5; Skeldon SC et al. Eur. Urol. 2013 Feb;63(2):379-85; Chui MH et al. Am. J. Surg. Pathol. 2014 Sep;38(9):1173-81; Rosty C et al. Fam. Cancer. 2014 Dec;13(4):573-82). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H;.;.;.
PhyloP100		7.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.8	D;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.98
MutPred		0.98		Gain of MoRF binding (P = 0.0714);.;Gain of MoRF binding (P = 0.0714);Gain of MoRF binding (P = 0.0714);
MVP		0.97
MPC		0.034
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.93
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: rs63750280; hg19: chr2-47702268;