2-47429886-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_000251.3(MSH2):c.1221C>T(p.Leu407Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 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 (★). Synonymous variant affecting the same amino acid position (i.e. L407L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0680

Publications

6 publications found

Variant links:

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

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (REVEL=0.015).

BP6

Variant 2-47429886-C-T is Benign according to our data. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47429886-C-T is described in CliVar as Likely_benign. Clinvar id is 3230808.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.068 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.1221C>T	p.Leu407Leu	synonymous_variant	Exon 7 of 16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.1221C>T	p.Leu407Leu	synonymous_variant	Exon 7 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111954

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:1

Oct 05, 2023

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.8

(source)

DANN

Benign

0.85

PhyloP100

-0.068

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over