Classification rationale

PP3 BS1 VUS

MSH2 c.1847C>G missense · exon 12

VUS: PP3 moderate because the MSH2 HCI prior probability for p.Pro616Arg is 0.900, above the >0.81 moderate cutoff. VUS: BS1 strong because the gnomAD v4.1 Grpmax FAF of 0.00018 falls inside the framework's 0.0001-0.001 benign-frequency window. VUS: BS1 (strong benign) together with PP3 (moderate pathogenic) matches the MSH2 v2.0 Rule22 conflicting-evidence combination.

PP3 + BS1 → VUS

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_000251.3 · variants mapped to exon structure

MSH2 NM_000251.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 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

PP3 moderate Pathogenic

Met at Moderate: the VCEP HCI prior probability for c.1847C>G (p.P616R) is 0.900, above the >0.81 PP3_Moderate cutoff.

cspec (ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specification for MSH2 v2.0) PP3 rules: 'Missense variant with HCI prior probability for pathogenicity >0.81 as per https://hci-priors.hci.utah.edu/PRIORS' = PP3_Moderate; 'Missense variant with HCI prior probability for pathogenicity >0.68 & <=0.81' = PP3_Supporting, the latter rule also carrying an alternative SpliceAI branch (delta score >= 0.2 for non-canonical splicing nucleotides) that is not applicable to this missense variant.hci_prior / vcep_hci_priors_msh2 (on-record HCI-PRIORS-MSH2.txt lookup table, the gene-specific PP3/BP4 supporting material declared by this gene's VCEP index): exact row found by grep for c.1847C>G, p.P616R at line 4078 of vcep_db/MSH2/fulltext/HCI-PRIORS-MSH2.txt.txt - exon 12, c.1847C>G, protein p.P616R, Custom_PP2_score (HCI prior probability of pathogenicity) 0.900, MAPP_score 41.48, MAPP/PP2_Prior 0.9565, reference {PMID22949387:Thompson et al., 2013}, DBID MSH2_04077. The variant is therefore not absent from the governing table; the pre-assigned code is read off that exact row.The same row confirms the amino-acid substitution: the table is keyed by coding substitution and lists c.1847C>G (p.P616R) explicitly, matching the case's normalized HGVS NP_000242.1:p.(Pro616Arg).

cspec ↗

BS1 strong Benign

Met at Strong: gnomAD v4.1 Grpmax FAF 0.00018 falls inside the InSiGHT MSH2 v2.0 BS1 window of 0.0001-0.001.

InSiGHT MSH2 v2.0 cspec BS1 rule (Benign Strong): 'GnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%) and variant is excluded as founder pathogenic variant.'gnomAD v4.1 (governing dataset named by the VCEP): joint Grpmax FAF 0.00017995, exome Grpmax FAF 0.00022385, genome Grpmax FAF 0.00001171, total AF 3.22189e-05 (52/1,613,962 alleles). The Grpmax FAF is the VCEP-specified metric and lands in the required 0.0001-0.001 band.gnomAD v2.1 (older build, context): Grpmax FAF 0.00015644 and total AF 6.71725e-05, also within the same order of magnitude; homozygotes 0.

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

Assessed · not applied · 9 not met · 6 not assessed

Pathogenic

PVS1 Not met: c.1847C>G is a missense substitution (p.Pro616Arg) with no PTC, frameshift or protein-length change and SpliceAI max delta 0.001.

PS1 Not met: codon 616 is CCT and only c.1847C>G encodes p.Pro616Arg, so no alternate nucleotide change exists for the PS1 comparator.

PS2 Not assessed: no proband, parental confirmation, or Lynch-spectrum tumour data exists to award any MSH2 de novo points (0.5 points minimum).

PS3 Not assessed: the approved calibrated MSH2 assay defines abnormal function as LoF score >0.4, but no variant-specific score is reported for p.(Pro616Arg).

PM2 Not met: gnomAD v4.1 all-allele frequency 3.22e-05 exceeds the InSiGHT MSH2 v2.0 PM2 cutoff of <0.00002.

PM3 Not met: no co-occurrence with a pathogenic/likely pathogenic MSH2 variant in a CMMRD-featured patient, scoring 0 points versus the 0.5-point Supporting threshold.

PM5 Not met: all five alternative codon-616 substitutions in ClinVar are Uncertain significance, Likely benign or conflicting, and none is classified Pathogenic or Likely Pathogenic by the VCEP.

PP1 Not assessed: no pedigree or segregation Bayes likelihood ratio exists to compare with the PP1 Supporting threshold of >2.08.

PP4 Not met: 0 documented MSI-H tumors with concordant MMR protein loss against the minimum PP4_Supporting requirement of 1 (0 >= 1 is false).

Benign

BA1 Not met: gnomAD v4.1 Grpmax FAF 0.00018 is ~5.6-fold below the InSiGHT MSH2 v2.0 BA1 stand-alone cutoff of 0.001.

BS2 Not assessed: no parental or offspring phase testing showing in-trans co-occurrence with a pathogenic MSH2 variant, which is what MSH2 v2.0 BS2 requires.

BS3 Not assessed: the calibrated MSH2 assay defines normal function as LoF score <=0, but no variant-specific score is reported for p.(Pro616Arg).

BS4 Not assessed: no non-segregating relatives or Bayes likelihood ratio exists to compare with the BS4 Strong cutoff of <0.05.

BP4 Not met: the VCEP HCI prior for p.P616R is 0.900, far above the <0.11 BP4_Supporting threshold for MSH2 missense variants.

BP5 Not met: 0 qualifying MSS/no-MMR-loss tumors documented against BP5_Supporting's minimum of 2 (2 <= 0 is false) and 0 >= 4 required for BP5_Strong.

N/A · 11 PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.22189e-05; MAF= 0.00322%, 52/1613962 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000328731; MAF= 0.03287%, 2/6084 alleles, homozygotes = 0); grpmax FAF= 0.00017995.

v2.1

This variant is present in gnomAD v2.1 (AF= 6.71725e-05; MAF= 0.00672%, 19/282854 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000310401; MAF= 0.03104%, 11/35438 alleles, homozygotes = 0); grpmax FAF= 0.00015644.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0032% · 52 / 1,613,962
0 hom · FAF 0.018%

Middle Eastern 2 / 6,084	0.033%
Admixed American 17 / 60,002	0.028%
European (non-Finnish) 32 / 1,179,994	0.0027%
Remaining individuals 1 / 62,480	0.0016%

+ 6 not observed (European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0067% · 19 / 282,854
0 hom · FAF 0.016%

Admixed American 11 / 35,438	0.031%
Remaining individuals 2 / 7,224	0.028%
European (non-Finnish) 6 / 129,172	0.0046%

+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), 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 Uncertain significance (7 clinical laboratories) and as Likely benign (5 clinical laboratories) and as likely benign (2 clinical laboratories) and as Benign (2 clinical laboratories). (ClinVarID = 127636)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.84. BayesDel score = 0.462389. HCI prior probability for pathogenicity = 0.9565. MAPP score = 41.48. Custom PP2 score = 0.9.

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. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial 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 previously been reported in somatic cancers (COSMIC; COSV99028441, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

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.

32849802 ↗ Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

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

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

28135145 ↗ Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. CLINVAR

28944238 ↗ Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. CLINVAR

31265121 ↗ Whole-exome sequencing of ovarian cancer families uncovers putative predisposition genes. CLINVAR

33357406 ↗ Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. CLINVAR

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