Classification rationale

BP7BP4 Likely Benign

PMS2 c.1128A>C

The PMS2 c.1128A>C (p.Pro376=) variant has been observed once in somatic cancers in COSMIC and has been reported in ClinVar predominantly as likely benign or benign by multiple single-submitter clinical laboratories.¹ This variant is present in gnomAD v2.1 and v4.1 at low frequency and is absent from gnomAD-Canada; the v4.1 allele frequency is 7.50e-05 (121/1612348 alleles) with a highest observed population frequency of 9.93e-05 in non-Finnish Europeans, which is above the PMS2 PM2_Supporting cutoff of 0.00002 but below the BS1 and BA1 population thresholds.² SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, supporting BP4 and BP7 for this synonymous change.³

BP7 + BP4 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

3 spliceai ↗cspec ↗

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

PMS2 NM_000535.7

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 13 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BP4 supporting Benign

For this synonymous variant, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.1; this supports BP4.

SpliceAI max delta score 0.00.

cspec ↗spliceai ↗

✓

BP7 supporting Benign

This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the benign splicing threshold of 0.1; this supports BP7.

Synonymous change p.(Pro376=).SpliceAI max delta score 0.00.

cspec ↗spliceai ↗

Assessed · not applied

Pathogenic

PS2 No confirmed de novo data were identified, so PS2 cannot be assessed.

PS3 No validated functional or RNA assay evidence showing a damaging effect was identified for this variant, so PS3 cannot be assessed.

PM2 This variant is present in gnomAD v4.1 at AF 7.50e-05 (121/1612348 alleles), which is above the PMS2 PM2_Supporting threshold of 0.00002; PM2 is not met.

PM3 No qualifying in trans observations for the recessive constitutional mismatch repair deficiency framework were identified, so PM3 cannot be assessed.

PP1 No segregation data were identified, so PP1 cannot be assessed.

PP3 This synonymous variant does not meet the PMS2 missense HCI-prior rule, no HCI prior entry was available for c.1128A>C, and SpliceAI predicts no splice defect with a maximum delta score of 0.00, which is below the PP3 splice threshold of 0.2; PP3 is not met.

PP4 No tumor microsatellite instability or mismatch-repair immunohistochemistry data were identified for this variant, so PP4 cannot be assessed.

Benign

BA1 The highest observed population frequency in gnomAD v4.1 is 9.93e-05 (0.00993%) in non-Finnish Europeans, which is below the BA1 threshold of 0.0028 (0.28%); BA1 is not met.

BS1 The highest observed population frequency in gnomAD v4.1 is 9.93e-05 (0.00993%) in non-Finnish Europeans, which is below the BS1 range of 0.00028 to 0.0028; BS1 is not met.

BS2 No confirmed in trans co-occurrence with a pathogenic PMS2 variant in an older individual without features of constitutional mismatch repair deficiency was identified, so BS2 cannot be assessed.

BS3 No validated functional or RNA assay evidence showing normal function or no mRNA aberration was identified for this variant, so BS3 cannot be assessed.

BS4 No non-segregation data were identified, so BS4 cannot be assessed.

BP5 No tumor evidence showing microsatellite-stable disease, retained mismatch-repair protein expression, or protein loss inconsistent with PMS2 was identified, so BP5 cannot be assessed.

N/A · 13 PVS1 · PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 7.50458e-05; MAF= 0.00750%, 121/1612348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.92624e-05; MAF= 0.00993%, 117/1178694 alleles, homozygotes = 0); grpmax FAF= 8.433e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.58175e-05; MAF= 0.00358%, 9/251274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.91431e-05; MAF= 0.00791%, 9/113718 alleles, homozygotes = 0); grpmax FAF= 4.115e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0075% · 121 / 1,612,348
0 hom · FAF 0.0084%

European (non-Finnish) 117 / 1,178,694	0.0099%
Remaining individuals 4 / 62,394	0.0064%

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

gnomAD v2.1

0.0036% · 9 / 251,274
0 hom · FAF 0.0041%

European (non-Finnish)

9 / 113,718

0.0079%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Likely Benign (2 clinical laboratories) and as Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory). (ClinVarID = 135932)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56224632, n = 1 times).

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 · 9 PMIDs not cited in assessment

25070057 ↗ Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. CLINVAR

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. 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

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

31672839 ↗ Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. CLINVAR

11598466 ↗ Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

20301390 ↗ Lynch Syndrome. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?