rs28929483

Variant names:

• chr2-47475130-C-A
• rs28929483
• NM_000251.3:c.1865C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47475130-C-A
• chr2-47475130-C-G
• chr2-47475130-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.1865C>A​(p.Pro622Gln) 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. P622L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a region_of_interest Interaction with EXO1 (size 70) in uniprot entity MSH2_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) 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 chr2-47475130-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 2-47475130-C-A is Pathogenic according to our data. Variant chr2-47475130-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427606.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.1865C>A	p.Pro622Gln	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.1865C>A	p.Pro622Gln	missense_variant	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colon cancer Pathogenic:1

Jul 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.1865C>A (p.Pro622Gln) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes. c.1865C>A has been reported in the literature in at least one individual with a history of colon cancer and suspected Lynch syndrome (e.g. Brand_2020). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1865C>T, p.P622L), supporting the critical relevance of codon 622 to MSH2 protein function. Several publications reports experimental evidence evaluating an impact on protein function. In human cell lines, the variant showed chemical insensitivity in the presence of toxic 6-TG targeting MMR-proficient cells, suggesting a loss of function effect of the variant (e.g. Jia_2021). In yeast model system, chemostat continuous culture assay showed mutation rates ~4-fold of WT for the variant, additionally suggestive of loss of function (e.g. Ollodart_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31997046, 33848333, 33357406). ClinVar contains an entry for this variant (Variation ID: 427606). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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: 33357406]. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jun 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 622 of the MSH2 protein (p.Pro622Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colon cancer (PMID: 31997046). ClinVar contains an entry for this variant (Variation ID: 427606). 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 with a positive predictive value of 95%. This variant disrupts the p.Pro622 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8261515, 16616355, 17720936, 21309037, 22283331, 24362816, 25117503). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 12, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P622Q variant (also known as c.1865C>A), located in coding exon 12 of the MSH2 gene, results from a C to A substitution at nucleotide position 1865. The proline at codon 622 is replaced by glutamine, an amino acid with similar properties. This variant was identified in an individual whose family history met Amsterdam II criteria for Lynch syndrome (Ambry internal data). This variant was also detected in a 39-year-old patient with colorectal cancer that demonstrated loss of MHS2 staining by immunohistochemistry (IHC) (Brand RE et al. Fam Cancer, 2020 Apr;19:169-175). 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). Other alterations at the same amino acid position, p.P622T as well as p.P622L, have been reported as likely pathogenic and pathogenic, respectively, based on identification in individuals meeting diagnostic criteria for Lynch syndrome, segregation with disease, and reduced mismatch repair function (Chialina SG et al. BMC Med. Genet. 2006 Jan 20;7:5; Rosty C et al. Fam. Cancer. 2014 Dec;13(4):573-82; Van de Water NS et al. Aust. N Z J Med. 1994 Dec;24:682-6; Jenkins MA et al. Int. J. Cancer 2002 Nov;102:166-71; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Schofield L et al. Int. J. Cancer 2009 Mar;124:1097-102; Arnold S et al. Hum. Mutat., 2009 May;30:757-70; Gammie AE et al. Genetics 2007 Oct;177:707-21; Lützen A et al. Mutat. Res. 2008 Oct;645:44-55; Mastrocola AS et al. Hum. Mutat. 2010 Oct;31:E1699-708; Wielders EA et al. Hum. Mutat. 2011 Apr;32:389-96; Drost M et al. Hum. Mutat. 2012 Mar;33:488-94; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). Based on an internal structural analysis using published crystal structures, this variant is more disruptive than known nearby pathogenic variants (Gupta S et al. Nat. Struct. Mol. Biol., 2011 Dec;19:72-8). This variant is considered to be rare based on population 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. 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	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H;.;.;.
PrimateAI	Uncertain	0.59	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 = 0.0606);.;Gain of MoRF binding (P = 0.0606);Gain of MoRF binding (P = 0.0606);
MVP		0.97
MPC		0.036
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs28929483; hg19: chr2-47702269; COSMIC: COSV51877870; COSMIC: COSV51877870;