Classification rationale

BS1BP4 Likely Benign

PMS2 c.1567T>A missense · exon 11

Likely Benign: BS1 (strong) - gnomAD v4.1 grpmax filtering allele frequency 0.00045665 falls within the PMS2 VCEP BS1 range. Likely Benign: BP4 (supporting) - the PMS2 VCEP HCI prior probability is 0.0008, below the <0.11 cutoff.

BS1 + BP4 → Likely Benign

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000535.7 · variants mapped to exon structure

PMS2 NM_000535.7

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BS1 strong Benign

Met, Strong: gnomAD v4.1 grpmax FAF is 0.00045665, within the PMS2 VCEP BS1 range of 0.00028 to less than 0.0028.

The PMS2 VCEP specifies BS1 Strong at gnomAD v4 grpmax filtering allele frequency ≥0.00028 and <0.0028 (0.028–0.28%), provided the variant is not an excluded founder pathogenic variant.gnomAD v4.1 reports grpmax FAF 0.00045665 (0.045665%), corresponding to 3 alleles in the highest grpmax population, and reports zero homozygotes.

cspec ↗gnomad_v4 ↗

BP4 supporting Benign

Met, Supporting: the governing PMS2 HCI prior probability is 0.0008, below the VCEP BP4 cutoff of <0.11.

The governing PMS2 VCEP specifies BP4 Supporting for a missense variant with HCI MAPP/PP2 Prior P <0.11.The exact HCI-PRIORS-PMS2 row for c.1567T>A / p.S523T reports HCI prior probability 0.0008 and custom PP2 score 0.031, satisfying the VCEP BP4 rule.

cspec ↗

Assessed · not applied · 5 not met · 9 not assessed

Pathogenic

PS1 Not met: the only reported alternate-nucleotide Ser523Thr observation was not established as Pathogenic by the PMS2 VCEP.

PS2 Not assessed: no proband-level parental testing, de novo confirmation, LS-spectrum tumor, or tumor MSI/IHC evidence is available to assign VCEP de novo points.

PS3 Not assessed: no variant-specific functional assay or calibrated functional odds are reported for PMS2 p.Ser523Thr.

PM2 Not met: gnomAD v4.1 overall AF is 0.000167304, above the PMS2 VCEP PM2 threshold of less than 0.00002.

PM3 Not assessed: no affected-proband, homozygous, or phase-resolved in-trans pathogenic PMS2 observation is documented to assign VCEP PM3 points.

PM5 Not met: zero qualifying Pathogenic or Likely Pathogenic same-residue comparators were identified for Ser523.

PP1 Not assessed: no pedigree, informative meioses, phenotype-linked genotypes, or combined Bayes likelihood ratio is reported for PP1 evaluation.

PP3 Not met: the governing PMS2 HCI prior probability is 0.0008, below the VCEP PP3 Supporting threshold of >0.68.

PP4 Not assessed: no case-specific CRC/endometrial tumor count or qualifying MSI-H and PMS2-consistent protein-loss result is available for the PP4 thresholds.

Benign

BA1 Not met: gnomAD v4.1 grpmax FAF is 0.00045665, below the PMS2 VCEP BA1 threshold of 0.0028.

BS2 Not assessed: no qualifying in-trans pathogenic variant, age-specific cancer phenotype, CMMRD assessment, or confirmed phase data are available.

BS3 Not assessed: no variant-specific protein, RNA, MMR activity, or calibrated functional assay demonstrates proficient function for p.Ser523Thr.

BS4 Not assessed: no non-segregating affected relative, informative pedigree data, or combined Bayes likelihood ratio is reported for BS4 evaluation.

BP5 Not assessed: no case-specific MSS, MMR-protein, BRAF V600E, or MLH1-methylation findings are available for the BP5 tumor-count thresholds.

N/A · 12 PVS1 · PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000167304; MAF= 0.01673%, 270/1613828 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000581995; MAF= 0.05820%, 53/91066 alleles, homozygotes = 0); grpmax FAF= 0.00045665.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000162798; MAF= 0.01628%, 46/282558 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000457277; MAF= 0.04573%, 14/30616 alleles, homozygotes = 0); grpmax FAF= 0.00027587.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.017% · 270 / 1,613,828
0 hom · FAF 0.046%

South Asian 53 / 91,066	0.058%
European (non-Finnish) 198 / 1,179,914	0.017%
Remaining individuals 6 / 62,504	0.0096%
Admixed American 4 / 59,966	0.0067%
European (Finnish) 4 / 63,952	0.0063%
African/African American 4 / 74,974	0.0053%
East Asian 1 / 44,874	0.0022%

+ 3 not observed (Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.016% · 46 / 282,558
0 hom · FAF 0.028%

South Asian 14 / 30,616	0.046%
European (non-Finnish) 28 / 129,000	0.022%
Remaining individuals 1 / 7,216	0.014%
European (Finnish) 2 / 25,116	0.008%
Admixed American 1 / 35,436	0.0028%

+ 3 not observed (African/African American, Ashkenazi Jewish, East Asian)

gnomAD Canada 🇨🇦

0.016% · 3 / 18,420
0 hom · FAF 0.0069%

European (non-Finnish)

3 / 11,740

0.026%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Uncertain significance (5 clinical laboratories) and as likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 127763)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.262. BayesDel score = -0.405143. HCI prior probability for pathogenicity = 0.0008. MAPP score = 2.35. Custom PP2 score = 0.031.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PMS2, an endonuclease involved in DNA repair, is altered in various cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

17016615 ↗ The mismatch repair gene hPMS2 is mutated in primary breast cancer. CLINVAR

17060676 ↗ ASCO 2006 update of recommendations for the use of tumor markers in gastrointest CLINVAR

22167527 ↗ Identification of individuals at risk for Lynch syndrome using targeted evaluati CLINVAR

22290698 ↗ Classification of mismatch repair gene missense variants with PON-MMR. CLINVAR

25006736 ↗ Multitarget stool DNA testing for colorectal-cancer screening. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26232782 ↗ A case of early onset rectal cancer of Lynch syndrome with a novel deleterious PMS2 mutation. CLINVAR

26845104 ↗ Improving performance of multigene panels for genomic analysis of cancer predisp CLINVAR

Check your email

Reset your password

Enter an access code

Your allowance