GeneBe

rs63749831

Variant names:
Germline classificationCancer classification (beta)

Variant summary

Our verdict is
Pathogenic
>+14 Pathogenic
-7
-6
-1
0
+5
+6
+9
+10
B
LB
VUS
LP
P
. The variant received 16 ACMG points: 16P and 0B. PS3PM1_SupportingPM2PM4_SupportingPP5_Very_Strong

The NM_000251.3(MSH2):c.1786_1788delAAT (p.Asn596del) variant causes a conservative inframe deletion change. The variant results in an in-frame change. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,262 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000009. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.51). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000919714: At least one publication reports experimental evidence evaluating an impact on protein function (Heinen_2003, Drost_2011, Heinen_2002)." and additional evidence is available in ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:20O:1

Conservation

PhyloP100: 8.51

Publications

33 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: ClinGen, Orphanet, G2P
  • Lynch syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • 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)
  • Muir-Torre syndrome
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • 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

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000251.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3
Well-established functional study supports damaging effect (PS3); SCV000919714: At least one publication reports experimental evidence evaluating an impact on protein function (Heinen_2003, Drost_2011, Heinen_2002).; SCV004827333: Functional studies have found the variant protein to be defective in DNA mismatch repair, ATP binding and ATPase assays (PMID: 12124176, 22102614).; SCV000684976: Functional studies have found the variant protein to be defective in DNA mismatch repair, ATP binding and ATPase assays (PMID: 12124176, 22102614).; SCV000211230: Published functional studies support a damaging effect: reduced DNA mispair recognition, binding, and ATP hydrolysis, and causing deficient mismatch repair activity (Heinen 2002, Drost 2012).; SCV001469802: in vitro studies indicated that the variant results in defective DNA repair, ATP binding and ATPase assay (PMIDs: 12124176 (2002), 22102614 (2012)).; SCV000255273: Experimental studies have shown that this variant affects MSH2 function (PMID: 12124176, 22102614).
PM1
Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 12 pathogenic, 23 benign (OR vs. background: 2.7).
PM2
Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000009 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00268) — PM2 moderate.
PM4
Single amino-acid in-frame indel in non-repetitive region — protein length change, supporting (PM4 +1); In-frame indel in non-repetitive region — protein length change (1 AA).
PP5
ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s).

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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
MSH2
NM_000251.3
MANE Select
c.1786_1788delAATp.Asn596del
conservative_inframe_deletion
Exon 12 of 16NP_000242.1P43246-1
MSH2
NM_001406674.1
c.1786_1788delAATp.Asn596del
conservative_inframe_deletion
Exon 12 of 18NP_001393603.1
MSH2
NM_001406631.1
c.1786_1788delAATp.Asn596del
conservative_inframe_deletion
Exon 12 of 18NP_001393560.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
MSH2
ENST00000233146.7
TSL:1 MANE Select
c.1786_1788delAATp.Asn596del
conservative_inframe_deletion
Exon 12 of 16ENSP00000233146.2P43246-1
MSH2
ENST00000406134.5
TSL:1
c.1786_1788delAATp.Asn596del
conservative_inframe_deletion
Exon 12 of 16ENSP00000384199.1E9PHA6
MSH2
ENST00000918107.1
c.1837_1839delAATp.Asn613del
conservative_inframe_deletion
Exon 13 of 17ENSP00000588166.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251458
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461262
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
726978
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33462
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39688
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86226
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111474
Other (OTH)
AF:
0.00
AC:
0
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
32

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
7
-
-
not provided (7)
5
-
-
Lynch syndrome 1 (6)
3
-
-
Lynch syndrome (3)
2
-
-
Hereditary cancer-predisposing syndrome (2)
1
-
-
Carcinoma of colon (1)
1
-
-
Hereditary nonpolyposis colorectal neoplasms (1)
1
-
-
MSH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
8.5
Mutation Taster
=16/84
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
Splicevardb
1.0
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.

Publications

Other links and lift over

dbSNP: rs63749831;
hg19: chr2-47702189;
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