2-47466718-G-C

Variant names:

• chr2-47466718-G-C
• rs63751207
• NM_000251.3:c.1571G>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.1571G>C​(p.Arg524Pro) 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 (★★★). ClinVar reports functional evidence for this variant: "SCV004186687: Functional studies indicate this variant impacts protein function [PMID:12124176, 20672385, 28422960]." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R524G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.06
• Publications: 33 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

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004186687: Functional studies indicate this variant impacts protein function [PMID: 12124176, 20672385, 28422960].; SCV000216385: Multiple functional assays have demonstrated that this protein was repair-deficient, unstable, and unable to elicit a DNA checkpoint in response to DNA alkylation damage (Boyer JC et al. Cancer Res. 1995 Dec; 55(24):6063-70; Mastrocola AS et al. Hum. Mutat. 2010 Oct; 31(10):E1699-708; Nielsen SV et al. PLoS Genet. 2017 Apr 19;13(4):e1006739).; SCV000684947: Functional studies have shown that this variant reduces interactions with MSH3 or MSH6 and impairs mismatch repair (MMR) activities (PMID: 8521394, 12124176, 17594722, 20672385).; SCV000322357: "Published functional studies demonstrate a damaging effect: defective mismatch repair, abolishment of the dominant mutator phenotype, deficient ATPase activity, reduced mismatch-binding in vitro and MNNG-induced chromatin-binding in cells, and decreased MMR protein complex assembly (PMID: 8521394, 9774676, 9889267, 10469597, 12124176, 20672385, 33357406)"; SCV000889416: Experimental studies have demonstrated a damaging effect on MSH2 protein function (PMID: 7937795 (1994), 8521394 (1995), 10469597 (1999), 12124176 (2002), 17594722 (2007), 17720936 (2007), 20672385 (2010), 33357406 (2021)).; SCV000625286: Experimental studies have shown that this missense change affects MSH2 function (PMID: 7937795, 10469597, 17594722, 20672385).; SCV000919690: Several publications report experimental evidence evaluating an impact on protein function (e.g. Drotschmann_1999, Heinen_2002, Gammie_2007, Mastrocola_2010).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 22 benign, 31 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 chr2-47466717-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1775501.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 2-47466718-G-C is Pathogenic according to our data. Variant chr2-47466718-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1759.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.1571G>C	p.Arg524Pro	missense	Exon 10 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1571G>C	p.Arg524Pro	missense	Exon 10 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1571G>C	p.Arg524Pro	missense	Exon 10 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.1571G>C	p.Arg524Pro	missense	Exon 10 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1571G>C	p.Arg524Pro	missense	Exon 10 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1622G>C	p.Arg541Pro	missense	Exon 11 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Lynch syndrome (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Lynch syndrome 1 (2)
2	-	-	not provided (2)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.86		Loss of catalytic residue at R524 (P = 0.0336)
MVP		0.99
MPC		0.031
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63751207; hg19: chr2-47693857;