Starting
Initialising…
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MSH3
Final classification
VUS
MSH3 c.2436-13G>T · p.?
MSH3

The MSH3 c.2436-13G>T (p.?) variant has been reported in ClinVar as Likely benign.

Gene
MSH3
Transcript
NM_002439.5
HGVS · transcript:coding
NM_002439.5:c.2436-13G>T
Consequence
N/A
GRCh38
chr5:80787552 G>T
GRCh37
chr5:80083371 G>T
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting; combination = 1 supporting benign, which maps to VUS. ▾
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting; combination = 1 supporting benign, which maps to VUS.
Classification rationale
BP4 VUS
MSH3 c.2436-13G>T

The MSH3 c.2436-13G>T (p.?) variant has been reported in ClinVar as Likely benign.1 This variant is present in population databases, including gnomAD v2.1 at 0.07852% overall with a highest observed population frequency of 0.14797% and gnomAD v4.1 at 0.13248% overall with a highest observed population frequency of 0.17028%, which is above a default PM2 rarity threshold of 0.1% but below default BS1 and BA1 thresholds.2 In silico splicing prediction does not support a damaging splice effect, with SpliceAI showing a maximum delta score of 0.02.3

BP4 → VUS
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 spliceai ↗
Gene diagram · NM_002439.5 · variants mapped to exon structure
MSH3 NM_002439.5
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 0.00132477; MAF= 0.13248%, 2106/1589706 alleles, homozygotes = 5) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00170283; MAF= 0.17028%, 1972/1158070 alleles, homozygotes = 5); grpmax FAF= 0.00164017.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 0.000785157; MAF= 0.07852%, 222/282746 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00147968; MAF= 0.14797%, 191/129082 alleles, homozygotes = 1); grpmax FAF= 0.00136914.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.13% · 2106 / 1,589,706
      5 hom · FAF 0.16%
      European (non-Finnish)
      1972 / 1,158,070
      0.17%
      5 hom
      Remaining individuals
      64 / 61,670
      0.1%
      Admixed American
      29 / 59,934
      0.048%
      Ashkenazi Jewish
      14 / 29,444
      0.048%
      African/African American
      17 / 74,390
      0.023%
      European (Finnish)
      8 / 63,950
      0.013%
      South Asian
      2 / 90,610
      0.0022%
      + 3 not observed (Amish, East Asian, Middle Eastern)
      gnomAD v2.1
      0.079% · 222 / 282,746
      1 hom · FAF 0.14%
      European (non-Finnish)
      191 / 129,082
      0.15%
      1 hom
      Ashkenazi Jewish
      6 / 10,368
      0.058%
      Remaining individuals
      3 / 7,220
      0.042%
      Admixed American
      13 / 35,420
      0.037%
      African/African American
      6 / 24,966
      0.024%
      European (Finnish)
      3 / 25,120
      0.012%
      + 2 not observed (East Asian, South Asian)
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely benign (3 clinical laboratories).
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
      SpliceAI ↗
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      COSMIC ↗
      Sources & reference links
      6Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC