chr2-47414389-G-A

Variant names:

• chr2-47414389-G-A
• rs63751454
• NM_000251.3:c.913G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. BS2 BS3_Supporting PP3_Moderate BP5 BS4_Supporting

This summary comes from the ClinGen Evidence Repository: The MSH2 c.913G>A variant is predicted as a missense variant, p.(Ala305Thr). Its MAPP+PolyPhen-2 prior probability for pathogenicity is >0.81 (http://priors.hci.utah.edu/PRIORS). It showed lack of co-segregation with disease with Bayes Likelihood Ratio >0.05 & ≤0.482 (Insight database). It was identified in 2 individuals with CRC showing MSS or inconsistent MMR protein expression pattern. It has been functionally analyzed in several studies: functional Odds for Pathogenicity is >0.05 & ≤0.482 (Drost et al., 2011 PMID 22102614); proficient function, expression and localization (PMID 18822302); proficient function (PMID 33357406). It has been identified in co-occurrence in trans with a MSH2 known pathogenic variant (Invitae internal data). Therefore, this variant is classified as likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA022539/MONDO:0005835/137

• Frequency:
  • Genomes: 𝑓 0.000077 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:9
• Conservation: PhyloP100: 7.72
• Publications: 18 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: Likely_benign. The variant received -5 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BS4: For more information check the summary or visit ClinGen Evidence Repository.

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.913G>A	p.Ala305Thr	missense	Exon 5 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.913G>A	p.Ala305Thr	missense	Exon 5 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.913G>A	p.Ala305Thr	missense	Exon 5 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.913G>A	p.Ala305Thr	missense	Exon 5 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.913G>A	p.Ala305Thr	missense	Exon 5 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.964G>A	p.Ala322Thr	missense	Exon 6 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0000768 AC: 9 AN: 117216 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000650

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000603 AC: 15 AN: 248830 AF XY: 0.0000595

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000156 AC: 205 AN: 1315136 Hom.: 0 Cov.: 37 AF XY: 0.000142 AC XY: 93 AN XY: 655584

African (AFR) AF: 0.0000668 AC: 2 AN: 29960

American (AMR) AF: 0.00 AC: 0 AN: 41706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22018

East Asian (EAS) AF: 0.00 AC: 0 AN: 32142

South Asian (SAS) AF: 0.00 AC: 0 AN: 83386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4444

European-Non Finnish (NFE) AF: 0.000193 AC: 193 AN: 1001306

Other (OTH) AF: 0.000192 AC: 10 AN: 52164

GnomAD4 genome AF: 0.0000768 AC: 9 AN: 117216 Hom.: 0 Cov.: 27 AF XY: 0.0000749 AC XY: 4 AN XY: 53416

African (AFR) AF: 0.0000650 AC: 2 AN: 30760

American (AMR) AF: 0.00 AC: 0 AN: 8268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.00 AC: 0 AN: 3472

South Asian (SAS) AF: 0.00 AC: 0 AN: 3410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.000113 AC: 7 AN: 61964

Other (OTH) AF: 0.00 AC: 0 AN: 1548

Alfa AF: 0.0000829 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	1	not specified (2)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Colorectal cancer, non-polyposis (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome (1)
-	-	1	Lynch syndrome 1 (1)
-	-	1	MSH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.94
MPC		0.036
ClinPred		0.84	D
GERP RS		4.2
Varity_R		0.77
gMVP		0.40
Mutation Taster		=6/94	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: rs63751454; hg19: chr2-47641528; COSMIC: COSV51877627; COSMIC: COSV51877627;