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MSH2c.1511-1G>AUncertain significance
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Variant interpretation report

MSH2 c.1511-1G>A, p.?

NM_000251.2:c.1511-1G>A NP_000242.1:p.? View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About MSH2

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is ClinGen MSH2 VCEP v2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

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.

PM2Supporting
PM2 · supporting

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).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.990 maximum delta

Recorded SpliceAI maximum delta score: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions

2 Pathogenic · 2 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 12 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000251.2:c.1511-1G>A is a canonical splice acceptor variant (IVS9-1G>A) in MSH2, absent from gnomAD population databases.

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).

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).

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.

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
  • Canonical IVS9-1G>A splice acceptor variant
  • SpliceAI max delta 0.99 (DS_AL=0.99
  • DS_AG=0.92)
  • Loss of function established disease mechanism for MSH2 under InSiGHT VCEP v2.0
  • Generic PVS1 framework (PMC6185798) confirms eligibility for canonical splice variants
Still missing
  • No patient RNA studies confirming splicing aberration or NMD
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗
PM2 SupportingThis 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). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 12 · evaluated, threshold not reached

PS2 No de novo observation data available for this variant in any reviewed publication or database. Details ▾Hide ▴
Still missing
  • No de novo points identified in ClinVar submissions or literature
PS3 No calibrated functional assay data or variant-specific experimental evidence is available for NM_000251.2:c.1511-1G>A. The VCEP MMR functional assay documentation covers calibrated assays for missense variants but no functional study has tested this specific splice variant. SpliceAI prediction alone is in silico evidence, not functional data. Details ▾Hide ▴
Evidence considered
  • SVI functional assay documentation does not include data for c.1511-1G>A
  • No PMID with variant-specific functional evidence identified
Still missing
  • No RNA studies or minigene assays for this variant
  • VCEP calibrated assays target missense variants primarily
Sources
vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data available for this variant in any reviewed family or pedigree. Details ▾Hide ▴
Still missing
  • No segregation analysis performed
PP4 No tumor MSI/IHC data specific to this variant is available. The ClinVar submissions (Variation ID 619529) report classifications of Pathogenic (2 labs) and Likely Pathogenic (2 labs) but do not provide patient-level tumor phenotype data for review. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 619529: Pathogenic (2 clinical labs)
  • Likely pathogenic (2 clinical labs)
  • No tumor MSI or IHC data available in any reviewed source
Still missing
  • No tumor phenotype data (MSI
  • IHC) available for ClinVar submissions
Sources
clinvar ↗
BA1 This variant is absent from gnomAD v4.1 (0 alleles). The InSiGHT VCEP BA1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%), which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1
Sources
gnomad_v4 ↗
BS1 This variant is absent from gnomAD v4.1. The InSiGHT VCEP BS1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%), which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1
Sources
gnomad_v4 ↗
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. Details ▾Hide ▴
Still missing
  • No co-occurrence data available
BS3 No variant-specific functional data demonstrating proficient function or normal splicing is available. SpliceAI predicts strong splicing impact (max delta 0.99), inconsistent with a benign functional effect. The VCEP functional assay documentation does not include data for this variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts strong acceptor loss (DS_AL=0.99)
  • inconsistent with normal splicing
  • No calibrated functional assay data for this variant
Still missing
  • No RNA studies demonstrating normal splicing
Sources
spliceai ↗vcep_functional_assay_svi_documentation_mmr
BS4 No co-segregation or lack-of-segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No segregation data available
BP4 Under the InSiGHT VCEP, BP4 for intronic variants requires SpliceAI delta score <= 0.1, indicating no splicing impact. This variant has a SpliceAI max delta score of 0.99, far exceeding the benign threshold. Not a missense variant, so HCI prior BP4 does not apply. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.99 exceeds the BP4 threshold of 0.1
Sources
spliceai ↗
BP5 No evidence of MSS tumors or inconsistent MMR protein expression is available for this variant. Details ▾Hide ▴
Still missing
  • No tumor phenotype data available
BP7 Under the InSiGHT VCEP, BP7 applies to intronic variants at or beyond -21/+7 (5'/3' exonic). This variant is at position c.1511-1 (IVS9-1), which is within the -21/+7 boundary, not beyond it. Additionally, SpliceAI predicts strong splicing impact (delta 0.99), which is inconsistent with a silent intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant at position -1 is within the -21/+7 splice region
  • not beyond it
  • SpliceAI max delta 0.99 predicts strong splicing impact
Sources
spliceai ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AVariant is a canonical splice site change, not a missense substitution; no other Pathogenic variant has been established at this same splice nucleotide by the VCEP. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPPS4 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPPM1 is designated Not Applicable by the InSiGHT MMR VCEP v2.0. Per VCEP instructions: 'There are no recognized mutational hot spots that could be used for classification purposes. While there are functional domains in the MMR genes, the distribution of pathogenic variants is generalized over all the domains.' Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies only to missense changes at an amino acid residue where a different missense change was classified as Pathogenic/Likely Pathogenic. This variant is a canonical splice site change, not a missense. pm5_candidates.json confirms not_applicable. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AUnder the InSiGHT MMR VCEP v2.0, PP3 for splice variants applies only to non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2. This variant (c.1511-1G>A) is a canonical IVS±1,2 splice site change. Additionally, the PVS1 rule explicitly states: 'Not to be combined with PP3.' Not a missense variant, so HCI prior PP3 does not apply. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPPP5 is designated Not Applicable for this VCEP by the InSiGHT MMR VCEP v2.0 specification: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' ClinVar review status is 'criteria provided, single submitter' (1-star), which would not meet the 3-star threshold for PP5 under generic rules. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPBP1 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 is designated Not Applicable by the InSiGHT MMR VCEP v2.0 specification; BS2 is used instead. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is designated Not Applicable for this VCEP by the InSiGHT MMR VCEP v2.0 specification: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not defined in the InSiGHT MMR VCEP v2.0 specification; variant is a canonical splice site change, not a missense substitution at an amino acid residue. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
MSH2
Transcript
NM_000251.2
Coding (HGVS c.)
NM_000251.2:c.1511-1G>A
Protein (HGVS p.)
NP_000242.1:p.?
GRCh38
chr2:47466657 G>A
GRCh37
chr2:47693796 G>A
ClinVar
619529

Gene diagram

Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.2. Select a row to find it on the plot.

MSH2NM_000251.2
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +1 bp
0.990
SpliceAI acceptor gainat +2 bp
0.920
SpliceAI donor lossat +69 bp
0.080
SpliceAI donor gainat +2 bp
0.000
Pangolin splice lossmagnitude shown
-0.870
Pangolin splice gain
0.860

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

BP4 Under the InSiGHT VCEP, BP4 for intronic variants requires SpliceAI delta score <= 0.1, indicating no splicing impact. This variant has a SpliceAI max delta score of 0.99, far exceeding the benign threshold. Not a missense variant, so HCI prior BP4 does not apply. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.99 exceeds the BP4 threshold of 0.1
Sources
spliceai ↗
BP7 Under the InSiGHT VCEP, BP7 applies to intronic variants at or beyond -21/+7 (5'/3' exonic). This variant is at position c.1511-1 (IVS9-1), which is within the -21/+7 boundary, not beyond it. Additionally, SpliceAI predicts strong splicing impact (delta 0.99), which is inconsistent with a silent intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant at position -1 is within the -21/+7 splice region
  • not beyond it
  • SpliceAI max delta 0.99 predicts strong splicing impact
Sources
spliceai ↗
PP3 N/AUnder the InSiGHT MMR VCEP v2.0, PP3 for splice variants applies only to non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2. This variant (c.1511-1G>A) is a canonical IVS±1,2 splice site change. Additionally, the PVS1 rule explicitly states: 'Not to be combined with PP3.' Not a missense variant, so HCI prior PP3 does not apply. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.
    Describes a method using somatic mutation variant read fractions from MMR-deficient tumors to classify constitutional MMR variants. NM_000251.2:c.1511-1G>A was not identified in this paper.
    Does not name this variant
    PMID 29887214 ↗
  • Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.
    CAPS Consortium consensus guidelines for pancreatic cancer surveillance in high-risk individuals, including Lynch syndrome patients with MLH1, MSH2, or MSH6 mutations. NM_000251.2:c.1511-1G>A was not identified in this paper.
    Does not name this variant
    PMID 31672839 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    National Society of Genetic Counselors practice recommendations for cancer genetic risk assessment and counseling. Does not discuss any specific MSH2 variant. NM_000251.2:c.1511-1G>A was not identified in this paper.
    Does not name this variant
    PMID 15604628 ↗
  • Lynch Syndrome.
    Adam MP et al. · 1993
    GeneReviews entry on Lynch Syndrome. Provides general clinical and genetic overview of Lynch syndrome. NM_000251.2:c.1511-1G>A was not identified in the available information for this reference.
    Does not name this variant
    PMID 20301390 ↗
  • ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
    Green RC et al. · 2013
    ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. Does not discuss any specific variant. NM_000251.2:c.1511-1G>A was not identified in this paper.
    Does not name this variant
    PMID 23788249 ↗
  • ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).
    Hegde M et al. · 2014
    ACMG technical standards and guidelines for genetic testing of inherited colorectal cancer (Lynch syndrome, FAP, MAP). Describes testing methods and mutation spectra at gene level. NM_000251.2:c.1511-1G>A was not identified in this paper.
    Does not name this variant
    PMID 24310308 ↗
  • Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
    Yurgelun MB et al. · 2015
    Multigene panel testing study identifying cancer predisposition gene mutations in patients with suspected Lynch syndrome. NM_000251.2:c.1511-1G>A was not identified in this paper.
    Does not name this variant
    PMID 25980754 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.990 Open source ↗
ClinVar 2 Pathogenic · 2 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories). (ClinVarID = 619529)

In silico

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

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).