2-47475127-G-C

Variant names:

• chr2-47475127-G-C
• rs759263820
• NM_000251.3:c.1862G>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5

The NM_000251.3(MSH2):​c.1862G>C​(p.Arg621Pro) 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000669850: This variant has been identified in multiple probands whose Lynch syndrome-associated tumors demonstrated loss of MSH2 and MSH6 expression by immunohistochemistry (Li S et al. J. Med. Genet. 2020 Jan" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R621Q) has been classified as Uncertain significance. 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.13
• Publications: 13 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000669850: This variant has been identified in multiple probands whose Lynch syndrome-associated tumors demonstrated loss of MSH2 and MSH6 expression by immunohistochemistry (Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Ambry internal data). The yeast equivalent of this variant demonstrated an increased mutation rate in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 Jun;218:).; SCV000946707: 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%.; SCV005623634: "The MSH2 c.1862G>C (p.Arg621Pro) variant has been reported in the published literature in functional studies that demonstrate this variant is damaging to mismatch repair function." PMID: 33848333 (2021), 33357406 (2021)
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 21 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 chr2-47475126-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408524.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 2-47475127-G-C is Pathogenic according to our data. Variant chr2-47475127-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 483736.

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.1862G>C	p.Arg621Pro	missense	Exon 12 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1862G>C	p.Arg621Pro	missense	Exon 12 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1862G>C	p.Arg621Pro	missense	Exon 12 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.1862G>C	p.Arg621Pro	missense	Exon 12 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1862G>C	p.Arg621Pro	missense	Exon 12 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1913G>C	p.Arg638Pro	missense	Exon 13 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.81		Gain of glycosylation at R621 (P = 0.0328)
MVP		0.94
MPC		0.031
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.97
Mutation Taster		=3/97	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: rs759263820; hg19: chr2-47702266;