2-47473818-C-T

Variant names:

• chr2-47473818-C-T
• rs3821227
• NM_000251.3:c.1760-1207C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000251.3(MSH2):​c.1760-1207C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 147,096 control chromosomes in the GnomAD database, including 18,476 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.49 (18476 hom., cov: 29)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.786
• Publications: 5 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, Orphanet, ClinGen
• 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: Orphanet, G2P, Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

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.1760-1207C>T		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1760-1207C>T		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1760-1207C>T		intron	N/A	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1760-1207C>T		intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1760-1207C>T		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1811-1207C>T		intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.488 AC: 71675 AN: 146994 Hom.: 18451 Cov.: 29

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.528

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.447

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.488 AC: 71757 AN: 147096 Hom.: 18476 Cov.: 29 AF XY: 0.492 AC XY: 35152 AN XY: 71470

African (AFR) AF: 0.668 AC: 27158 AN: 40664

American (AMR) AF: 0.406 AC: 5895 AN: 14524

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1163 AN: 3364

East Asian (EAS) AF: 0.679 AC: 3430 AN: 5050

South Asian (SAS) AF: 0.448 AC: 2037 AN: 4542

European-Finnish (FIN) AF: 0.532 AC: 5056 AN: 9502

Middle Eastern (MID) AF: 0.388 AC: 100 AN: 258

European-Non Finnish (NFE) AF: 0.385 AC: 25545 AN: 66288

Other (OTH) AF: 0.449 AC: 909 AN: 2026

Alfa AF: 0.388 Hom.: 13068

Bravo AF: 0.476

Asia WGS AF: 0.544 AC: 1889 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.24
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3821227;

hg19: chr2-47700957;