5-80654922-GCCCCCAGCT-GCCCCCAGCTCCCCCAGCT
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4
The NM_002439.5(MSH3):c.199_207dupCCAGCTCCC(p.Pro67_Pro69dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A70A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 20)
Exomes 𝑓: 0.000017 ( 1 hom. )
Consequence
MSH3
NM_002439.5 conservative_inframe_insertion
NM_002439.5 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0550
Publications
10 publications found
Genes affected
MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]
DHFR (HGNC:2861): (dihydrofolate reductase) Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]
DHFR Gene-Disease associations (from GenCC):
- constitutional megaloblastic anemia with severe neurologic diseaseInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_002439.5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH3 | NM_002439.5 | c.199_207dupCCAGCTCCC | p.Pro67_Pro69dup | conservative_inframe_insertion | Exon 1 of 24 | ENST00000265081.7 | NP_002430.3 | |
| DHFR | NM_000791.4 | c.-442_-434dupAGCTGGGGG | 5_prime_UTR_variant | Exon 1 of 6 | ENST00000439211.7 | NP_000782.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH3 | ENST00000265081.7 | c.199_207dupCCAGCTCCC | p.Pro67_Pro69dup | conservative_inframe_insertion | Exon 1 of 24 | 1 | NM_002439.5 | ENSP00000265081.6 | ||
| MSH3 | ENST00000667069.1 | c.199_207dupCCAGCTCCC | p.Pro67_Pro69dup | conservative_inframe_insertion | Exon 1 of 22 | ENSP00000499502.1 | ||||
| MSH3 | ENST00000670357.1 | n.199_207dupCCAGCTCCC | non_coding_transcript_exon_variant | Exon 1 of 25 | ENSP00000499791.1 | |||||
| DHFR | ENST00000439211.7 | c.-442_-434dupAGCTGGGGG | 5_prime_UTR_variant | Exon 1 of 6 | 1 | NM_000791.4 | ENSP00000396308.2 | |||
| MSH3 | ENST00000658259.1 | c.-272_-271insCCCCCAGCT | upstream_gene_variant | ENSP00000499617.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
20
GnomAD2 exomes AF: 0.0000237 AC: 3AN: 126454 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
126454
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000167 AC: 23AN: 1380954Hom.: 1 Cov.: 16 AF XY: 0.0000132 AC XY: 9AN XY: 683602 show subpopulations
GnomAD4 exome
AF:
AC:
23
AN:
1380954
Hom.:
Cov.:
16
AF XY:
AC XY:
9
AN XY:
683602
show subpopulations
African (AFR)
AF:
AC:
0
AN:
29094
American (AMR)
AF:
AC:
4
AN:
29760
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
23634
East Asian (EAS)
AF:
AC:
0
AN:
33142
South Asian (SAS)
AF:
AC:
2
AN:
78392
European-Finnish (FIN)
AF:
AC:
0
AN:
47962
Middle Eastern (MID)
AF:
AC:
1
AN:
5474
European-Non Finnish (NFE)
AF:
AC:
13
AN:
1076462
Other (OTH)
AF:
AC:
3
AN:
57034
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.449
Heterozygous variant carriers
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
20
Alfa
AF:
Hom.:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Endometrial carcinoma;C4310719:Familial adenomatous polyposis 4 Uncertain:1
Feb 29, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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