Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000535.7(PMS2):c.1753C>A (p.Leu585Ile)

CA010216

91313 (ClinVar)

Gene: PMS2
Condition: Lynch syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 0594a0af-c3ef-4b52-ad4e-3de7004f881f
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000535.7:c.1753C>A
NM_000535.7(PMS2):c.1753C>A (p.Leu585Ile)
NC_000007.14:g.5987012G>T
CM000669.2:g.5987012G>T
NC_000007.13:g.6026643G>T
CM000669.1:g.6026643G>T
NC_000007.12:g.5993169G>T
NG_008466.1:g.27095C>A
ENST00000699814.2:c.*1149C>A
ENST00000699840.2:c.1750C>A
ENST00000699930.2:c.1645C>A
ENST00000406569.8:c.1678+75C>A
ENST00000644110.2:c.*1347C>A
ENST00000699752.1:c.1597C>A
ENST00000699753.1:c.*1174C>A
ENST00000699754.1:c.1555C>A
ENST00000699755.1:c.*1152C>A
ENST00000699756.1:c.*1340C>A
ENST00000699757.1:c.*1010C>A
ENST00000699758.1:c.*1010C>A
ENST00000699759.1:n.2607C>A
ENST00000699760.1:c.1435C>A
ENST00000699761.1:c.1348C>A
ENST00000699762.1:c.1180C>A
ENST00000699763.1:c.*843C>A
ENST00000699764.1:c.*71C>A
ENST00000699765.1:c.*849C>A
ENST00000699766.1:c.1753C>A
ENST00000699767.1:c.1753C>A
ENST00000699768.1:c.1753C>A
ENST00000699811.1:c.1348C>A
ENST00000699813.1:n.1866C>A
ENST00000699814.1:c.1376C>A
ENST00000699815.1:c.*1284C>A
ENST00000699816.1:c.*643C>A
ENST00000699817.1:c.*1347C>A
ENST00000699818.1:c.1348C>A
ENST00000699819.1:c.*910C>A
ENST00000699820.1:c.1144+2788C>A
ENST00000699821.1:c.1348C>A
ENST00000699822.1:c.*1205C>A
ENST00000699823.1:c.1348C>A
ENST00000699824.1:c.*1256C>A
ENST00000699825.1:c.1192C>A
ENST00000699826.1:c.*1152C>A
ENST00000699827.1:c.1585C>A
ENST00000699828.1:c.*843C>A
ENST00000699833.1:n.3525C>A
ENST00000699837.1:c.1348C>A
ENST00000699838.1:c.*1653C>A
ENST00000699839.1:c.1939C>A
ENST00000699916.1:c.*1010C>A
ENST00000699917.1:c.*1202C>A
ENST00000699918.1:c.*1254C>A
ENST00000699919.1:c.*1340C>A
ENST00000699920.1:c.*1389C>A
ENST00000699928.1:c.989-4021C>A
ENST00000699929.1:c.*1054C>A
ENST00000699930.1:c.1645C>A
ENST00000699931.1:n.3181C>A
ENST00000699951.1:c.*849C>A
ENST00000699952.1:c.803+10314C>A
ENST00000699953.1:c.*860C>A
ENST00000699954.1:c.*1054C>A
ENST00000265849.12:c.1753C>A
ENST00000642292.1:c.1348C>A
ENST00000642456.1:c.1348C>A
ENST00000643595.1:c.*1152C>A
ENST00000644110.1:c.1435C>A
ENST00000265849.11:c.1753C>A
ENST00000382321.5:c.804-4021C>A
ENST00000406569.7:n.1678+75C>A
ENST00000441476.6:c.1435C>A
ENST00000469652.1:n.63-4107C>A
NM_000535.5:c.1753C>A
NR_003085.2:n.1835C>A
NM_000535.6:c.1753C>A
NM_001322003.1:c.1348C>A
NM_001322004.1:c.1348C>A
NM_001322005.1:c.1348C>A
NM_001322006.1:c.1597C>A
NM_001322007.1:c.1435C>A
NM_001322008.1:c.1435C>A
NM_001322009.1:c.1348C>A
NM_001322010.1:c.1192C>A
NM_001322011.1:c.820C>A
NM_001322012.1:c.820C>A
NM_001322013.1:c.1180C>A
NM_001322014.1:c.1753C>A
NM_001322015.1:c.1444C>A
NR_136154.1:n.1840C>A
NM_001322003.2:c.1348C>A
NM_001322004.2:c.1348C>A
NM_001322005.2:c.1348C>A
NM_001322006.2:c.1597C>A
NM_001322008.2:c.1435C>A
NM_001322009.2:c.1348C>A
NM_001322010.2:c.1192C>A
NM_001322011.2:c.820C>A
NM_001322012.2:c.820C>A
NM_001322013.2:c.1180C>A
NM_001322014.2:c.1753C>A
NM_001322015.2:c.1444C>A
NM_001322007.2:c.1435C>A
More

Uncertain Significance

Met criteria codes 2
BP4 PM2_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The NM_000535.7: c.1753C>A variant in PMS2 is a missense variant predicted to cause substitution of Leucin by Isoleucin at amino acid 585 (p. Leu585Ile). This alteration has been identified in cis with a pathogenic PMS2 mutation in an HNPCC/Lynch syndrome family and was shown to be mismatch-repair proficient in vitro (PMID: 16472587; 24027009). This alteration has been classified as a variant of unknown significance by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15;) The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is (3/268266 alleles) in the European (non-Finish) population, and the GnomAD v4.1 Grpmax AF is 0.000007310 which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore meets this criterion (PM2_Supporting). This missense variant meets the criteria for BP4 (Missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity <0.11). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM2_SUP, BP4 (VCEP specifications version 1)
Met criteria codes
BP4
This missense variant meets the criteria for PP3 (MAPP+PolyPhen-2 prior probability for pathogenicity >0.68 & ≤0.81). http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is (3/268266 alleles) in the European (non-Finish) population, which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore meets this criterion (PM2_Supporting). Update: GnomAD v4.1 Grpmax AF = 0.000007310
Curation History
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