Classification rationale

PVS1PM2 VUS

MSH2 c.1511-1G>A

NM_000251.2:c.1511-1G>A is a canonical splice acceptor variant (IVS9-1G>A) in MSH2, absent from gnomAD population databases.¹ PVS1 (very strong) is applied per the InSiGHT MMR VCEP v2.0 decision tree: variants at IVS±1 or IVS±2 where exon skipping disrupts reading frame and is predicted to undergo NMD. SpliceAI predicts strong acceptor loss (delta 0.99).² PM2 (supporting) is applied per InSiGHT VCEP: variant is absent from gnomAD v4.1, meeting the allele frequency threshold of <0.00002 (<1 in 50,000 alleles).³ This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and Likely Pathogenic (2 clinical laboratories); however, PP5 is not applied per VCEP rules.⁴

PVS1 + PM2 → VUS

1 cspec ↗gnomad_v4 ↗gnomad_v2 ↗spliceai ↗

2 cspec ↗pvs1_variant_assessment

3 gnomad_v4 ↗gnomad_v2 ↗

4 clinvar ↗

Gene diagram · NM_000251.2 · variants mapped to exon structure

MSH2 NM_000251.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 12 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

NM_000251.2:c.1511-1G>A is a canonical splice acceptor variant (IVS9-1G>A) in MSH2. Under the InSiGHT MMR VCEP v2.0 PVS1 decision tree, variants at IVS±1 or IVS±2 where exon skipping disrupts reading frame and is predicted to undergo NMD are assigned PVS1 (very strong). Loss of function is an established disease mechanism for MSH2. SpliceAI predicts strong splicing impact (max delta score 0.99, acceptor loss 0.99). Not combined with PP3 per VCEP rule.

Canonical IVS9-1G>A splice acceptor variantSpliceAI max delta 0.99 (DS_AL=0.99DS_AG=0.92)

cspec ↗spliceai ↗

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada v1.0, meeting the InSiGHT VCEP allele frequency threshold of <0.00002 (<1 in 50,000 alleles).

Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS2 No de novo observation data available for this variant in any reviewed publication or database.

PS3 No calibrated functional assay data or variant-specific experimental evidence is available for NM_000251.2:c.1511-1G>A.

PP1 No co-segregation data available for this variant in any reviewed family or pedigree.

PP4 No tumor MSI/IHC data specific to this variant is available.

Benign

BA1 This variant is absent from gnomAD v4.1 (0 alleles).

BS1 This variant is absent from gnomAD v4.1.

BS2 No evidence of co-occurrence in trans with a known pathogenic MSH2 variant in a patient with colorectal cancer after age 45 without CMMRD features, as required by the InSiGHT VCEP BS2 rule.

BS3 No variant-specific functional data demonstrating proficient function or normal splicing is available.

BS4 No co-segregation or lack-of-segregation data available for this variant.

BP4 Under the InSiGHT VCEP, BP4 for intronic variants requires SpliceAI delta score <= 0.1, indicating no splicing impact.

BP5 No evidence of MSS tumors or inconsistent MMR protein expression is available for this variant.

BP7 Under the InSiGHT VCEP, BP7 applies to intronic variants at or beyond -21/+7 (5'/3' exonic).

N/A · 11 PS1 · PS4 · PM1 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 Pathogenic (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories). (ClinVarID = 619529)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.66.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 7 PMIDs not cited in assessment

29887214 ↗ Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes. 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

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

20301390 ↗ Lynch Syndrome. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

24310308 ↗ ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). CLINVAR

25980754 ↗ Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. CLINVAR