2-47414361-C-T

Variant names:

• chr2-47414361-C-T
• rs201334592
• NM_000251.3:c.885C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000251.3(MSH2):​c.885C>T​(p.Asp295Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 1,580,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.60
• 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, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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: 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

Our verdict: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-47414361-C-T is Benign according to our data. Variant chr2-47414361-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.885C>T	p.Asp295Asp	synonymous	Exon 5 of 16	NP_000242.1
	MSH2	NM_001406674.1		c.885C>T	p.Asp295Asp	synonymous	Exon 5 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.885C>T	p.Asp295Asp	synonymous	Exon 5 of 18	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.885C>T	p.Asp295Asp	synonymous	Exon 5 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.885C>T	p.Asp295Asp	synonymous	Exon 5 of 16	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.885C>T	p.Asp295Asp	synonymous	Exon 5 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes AF: 0.0000149 AC: 2 AN: 134482 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000304

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445708 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718956

African (AFR) AF: 0.00 AC: 0 AN: 33012

American (AMR) AF: 0.00 AC: 0 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25544

East Asian (EAS) AF: 0.00 AC: 0 AN: 38520

South Asian (SAS) AF: 0.00 AC: 0 AN: 85954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5476

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1101340

Other (OTH) AF: 0.00 AC: 0 AN: 59212

GnomAD4 genome AF: 0.0000149 AC: 2 AN: 134482 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 63398

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 35686

American (AMR) AF: 0.00 AC: 0 AN: 11300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4498

South Asian (SAS) AF: 0.00 AC: 0 AN: 4350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 206

European-Non Finnish (NFE) AF: 0.0000304 AC: 2 AN: 65790

Other (OTH) AF: 0.00 AC: 0 AN: 1802

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 25, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Lynch syndrome 1 Benign:1

Dec 05, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

Hereditary nonpolyposis colorectal neoplasms Benign:1

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Mar 01, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	9.7
DANN	Benign	0.57
PhyloP100		1.6
Mutation Taster		=96/4	polymorphism

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: rs201334592; hg19: chr2-47641500;