MSH2c.67T>CBenign

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Variant interpretation report

MSH2 c.67T>C, p.(Phe23Leu)

NM_000251.3:c.67T>C NP_000242.1:p.(Phe23Leu) View identifiers

Classification

Benign

Variant description:

No variant summary was recorded for this case.

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

Benign.A benign classification under the recorded framework.

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 v2.0.0. 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: 0 Benign evidence criteria: 1

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1

BA1Stand alone

BA1 · stand alone

The variant exceeds the MSH2 VCEP BA1 frequency threshold in gnomAD v4.1. The grpmax filtering allele frequency is 0.00394201, above the BA1 cutoff of 0.001, with 410/1600398 alleles observed overall and 8 homozygotes. No founder pathogenic exception was identified in the reviewed sources.

Recorded classification: Benign

The explicit CSPEC/VCEP final-classification framework in final_classification_framework.json was used (source: cspec_ruleset; Richards et al. 2015 combining rules as represented in the retrieved CSPEC ruleset). Under this framework, BA1 (Stand Alone) satisfies the benign combination rule.

02The sources

Evidence at a glance

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

gnomAD v4.1

gnomAD v2.1

Population frequency

410 / 1,600,398 alleles

gnomAD v4.1: 410 / 1,600,398 alleles. Recorded AF 0.000256186. Recorded homozygote count 8.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000559062; MAF= 0.05591%, 141/252208 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00480596; MAF= 0.48060%, 133/27674 alleles, homozygotes = 2); grpmax FAF= 0.00414111.

Applied · BA1 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0.0, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 2 not met · 13 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PP4 PM5 PM2 PS1 PS2 PM1 PP5 PP1 PM6 PVS1 PS4 PM4 PS3 PP3 PM3 PP2

Benign

BP3 BP7 BS4 BS3 BP2 BP4 BP6 BS1 BP5 BA1 BS2 BP1

Met Not met Not assessed Not applicable

The MSH2 c.67T>C (p.Phe23Leu) variant has not been observed in COSMIC somatic cancer records and has been reported in ClinVar predominantly as benign or likely benign, with an aggregate ClinVar classification of Benign.

This variant is present at high frequency in population databases, including gnomAD v4.1 at 410/1600398 alleles with 8 homozygotes and grpmax filtering allele frequency 0.00394201, which exceeds the MSH2 VCEP BA1 threshold.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01; no missense-specific HCI prior value was available to support PP3 or BP4 assessment.

Met · 1

BA1 Stand aloneThe variant exceeds the MSH2 VCEP BA1 frequency threshold in gnomAD v4.1. The grpmax filtering allele frequency is 0.00394201, above the BA1 cutoff of 0.001, with 410/1600398 alleles observed overall and 8 homozygotes. No founder pathogenic exception was identified in the reviewed sources. Details ▾Hide ▴

Rule

BA1 requires gnomAD v4 grpmax filtering allele frequency >=0.001 and exclusion as a founder pathogenic variant.

Evidence considered

gnomAD v4.1 grpmax FAF 0.00394201; total AF 0.000256186; 410/1600398 alleles; 8 homozygotes
Highest observed subpopulation frequency in gnomAD v4.1 is 1KG:BEB AF 0.020202 (4/198 alleles)
ClinVar aggregate interpretation is Benign with multiple benign/likely benign submissions

Still missing

Manual confirmation that no founder pathogenic exception applies

Sources

gnomad_v4 ↗gnomad_v2 ↗clinvar ↗

Not met · 2 · evaluated, threshold not reached

PM2 The variant is not absent or extremely rare in population databases; gnomAD v4.1 shows total AF 0.000256186 with grpmax FAF 0.00394201, well above the PM2_Supporting threshold of <0.00002. Details ▾Hide ▴

Rule

PM2_Supporting requires absent/extremely rare allele frequency <0.00002 in gnomAD v4.

Evidence considered

gnomAD v4.1 total AF 0.000256186, 410/1600398 alleles, 8 homozygotes, grpmax FAF 0.00394201
gnomAD v2.1 total AF 0.000559062, 141/252208 alleles, 2 homozygotes

Sources

gnomad_v4 ↗gnomad_v2 ↗

BS1 The population frequency exceeds the BS1 range and instead falls into the BA1 range. gnomAD v4.1 grpmax FAF is 0.00394201, which is above the BS1 upper bound of <0.001. Details ▾Hide ▴

Rule

BS1 requires gnomAD v4 grpmax filtering allele frequency >=0.0001 and <0.001.

Evidence considered

gnomAD v4.1 grpmax FAF 0.00394201

Sources

gnomad_v4 ↗

Not assessed · 13 · no assessment recorded

PP4 No individual tumor MSI/IHC or phenotype data were identified to support PP4 under the MSH2 VCEP rules. Details ▾Hide ▴

Rule

1-3 independent CRC/endometrial MSI-H tumors and/or loss of MMR protein expression consistent with the variant location are required for PP4 strength assignment.

Still missing

Tumor MSI results
MMR protein expression results
Family-level count of independent qualifying tumors

BS4 No segregation data or Bayes likelihood ratio were identified. Details ▾Hide ▴

Rule

Requires lack of co-segregation with disease in pedigree(s) with combined Bayes LR below the specified threshold.

Still missing

Pedigree-level segregation data
Combined Bayes likelihood ratio

BS3 No variant-specific calibrated functional assay or qualifying RNA assay demonstrating proficient function was identified. Details ▾Hide ▴

Rule

Requires calibrated functional odds for pathogenicity <=0.48 or qualifying proficient protein/mRNA assay evidence per MMR flowchart.

Evidence considered

MMR VCEP materials were reviewed for PS3/BS3 framework, but no variant-specific assay result for c.67T>C was identified.

Still missing

Variant-specific calibrated MMR functional assay result
Variant-specific RNA assay result if relevant

Sources

vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t

PM5 No evidence was identified in the reviewed sources for a different pathogenic or likely pathogenic missense change at residue Phe23 that would satisfy PM5, and PP3 was not established. Details ▾Hide ▴

Rule

Requires a different missense change at the same residue already classified by the VCEP as pathogenic or likely pathogenic, with PP3 also met.

Still missing

Pathogenic/Likely pathogenic missense precedent at the same amino acid residue
Missense-specific PP3 evidence

BP4 For MSH2 missense variants, BP4 requires an HCI prior probability of pathogenicity <0.11; no HCI prior value was identified. The available SpliceAI result is not sufficient for missense BP4 under this VCEP rule. Details ▾Hide ▴

Rule

For missense variants, BP4 requires HCI prior probability <0.11.

Evidence considered

SpliceAI max delta score 0.01 predicts no significant splice impact

Still missing

HCI prior probability for p.Phe23Leu

Sources

spliceai ↗

PS1 No prior pathogenic or likely pathogenic nucleotide change encoding the same amino acid substitution was identified in the reviewed sources. Details ▾Hide ▴

Rule

Requires the same amino acid substitution or same non-canonical splice nucleotide as a previously established pathogenic/likely pathogenic variant under the VCEP rule.

Still missing

Confirmed VCEP pathogenic/likely pathogenic same-amino-acid precedent

PS2 No de novo data were identified. Details ▾Hide ▴

Rule

Requires de novo points sufficient for supporting, moderate, strong, or very strong evidence.

Still missing

Confirmed maternity and paternity
De novo points based on phenotype and testing context

PP1 No segregation data or Bayes likelihood ratio were identified to support co-segregation. Details ▾Hide ▴

Rule

Requires co-segregation with disease in pedigree(s) with combined Bayes LR above the specified threshold.

Still missing

Pedigree-level segregation data
Combined Bayes likelihood ratio

BP5 No tumor data showing MSS, retained MMR protein expression, or gene-inconsistent IHC loss were identified. Details ▾Hide ▴

Rule

Requires specified contradictory tumor features or MLH1 methylation/BRAF evidence per VCEP thresholds.

Still missing

Tumor MSI data
MMR IHC data
BRAF V600E or MLH1 methylation data if relevant

PS3 No variant-specific calibrated functional assay or qualifying MMR functional flowchart evidence demonstrating an MMR defect was identified for p.Phe23Leu. Details ▾Hide ▴

Rule

Requires calibrated functional odds for pathogenicity >2.08 or qualifying MMR functional defect evidence per VCEP rules.

Evidence considered

MMR VCEP materials were reviewed for PS3/BS3 framework, but no variant-specific qualifying assay result for c.67T>C was identified.

Still missing

Variant-specific calibrated MMR functional assay result
Variant-specific mRNA assay result if relevant

Sources

vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_tliterature_pass

PP3 For MSH2 missense variants, PP3 requires an HCI prior probability >0.68; no HCI prior value was identified. SpliceAI predicts no significant splice impact, but the splice-based PP3 rule applies to non-canonical splice nucleotides rather than this missense substitution. Details ▾Hide ▴

Rule

For missense variants, PP3 requires HCI prior probability >0.68; splice-based PP3 applies to non-canonical splice nucleotides with SpliceAI >=0.2.

Evidence considered

SpliceAI max delta score 0.01

Still missing

HCI prior probability for p.Phe23Leu

Sources

spliceai ↗

BS2 No confirmed in trans co-occurrence with a known pathogenic MSH2 variant in an appropriately phenotyped older individual was identified. Details ▾Hide ▴

Rule

Requires co-occurrence in trans with a known pathogenic sequence variant in a patient meeting the specified age and phenotype constraints and without evidence of CMMRD.

Still missing

Confirmed phase with a known pathogenic MSH2 variant
Clinical data excluding CMMRD features
Age-at-diagnosis data

Sources

vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s

PM3 No biallelic observation data or point-based PM3 evidence were identified. Details ▾Hide ▴

Rule

Requires PM3 point accumulation for recessive/CMMRD-style evidence.

Still missing

Observed in trans occurrences with another pathogenic MSH2 variant
PM3 point calculation data

Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴

BP3 N/ABP3 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists BP3 as not applicable.

Sources

cspec ↗

BP7 N/ANM_000251.3:c.67T>C is a missense variant, not a synonymous or qualifying deep intronic change. Details ▾Hide ▴

Rule

Applies to synonymous or intronic variants at or beyond -21/+7.

Evidence considered

Protein consequence NP_000242.1:p.(Phe23Leu)/p.(F23L)

Sources

prefetch

BP2 N/ABP2 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists BP2 as not applicable.

Sources

cspec ↗

BP6 N/ABP6 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists BP6 as not applicable.

Sources

cspec ↗

PM1 N/APM1 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists PM1 as not applicable.

Sources

cspec ↗vcep_m_m_r___f_u_n_c_t_i_o_n_a_l___d_o_m_a_i_n_s

PP5 N/APP5 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists PP5 as not applicable.

Sources

cspec ↗clinvar ↗

PM6 N/APM6 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists PM6 as not applicable.

Sources

cspec ↗

PVS1 N/ANM_000251.3:c.67T>C causes a missense substitution, p.(Phe23Leu), and is not a null variant or qualifying splice variant for PVS1. Details ▾Hide ▴

Rule

PVS1 applies to qualifying null variants or demonstrated splice defects under the MMR PVS1 framework.

Evidence considered

Protein consequence NP_000242.1:p.(Phe23Leu)/p.(F23L)

Sources

prefetchvcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___m_m_r

PS4 N/APS4 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists PS4 as not applicable.

Sources

cspec ↗

PM4 N/APM4 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists PM4 as not applicable.

Sources

cspec ↗

BP1 N/ABP1 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists BP1 as not applicable.

Sources

cspec ↗

PP2 N/APP2 is designated not applicable in the MSH2 VCEP specification. Details ▾Hide ▴

Evidence considered

MSH2 VCEP criterion table lists PP2 as not applicable.

Sources

cspec ↗

Identifiers

Gene: MSH2
Transcript: NM_000251.3
Coding (HGVS c.): NM_000251.3:c.67T>C
Protein (HGVS p.): NP_000242.1:p.(Phe23Leu)
GRCh38: chr2:47403258 T>C
GRCh37: chr2:47630397 T>C

Gene diagram

Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.3. Select a row to find it on the plot.

MSH2NM_000251.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in MSH2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 410 / 1,600,398 alleles AF 0.000256 · 8 homozygotes · FAF 0.00394

gnomAD v2.1 141 / 252,208 alleles AF 0.000559 · 2 homozygotes · FAF 0.00414

By genetic ancestry

gnomAD v4.1

AF 0.00026 · 410 / 1,600,398 alleles · 8 hom · FAF 0.0039

1KG:BEB4 / 198	0.02
1KG:STU2 / 196	0.01
1KG:ITU1 / 204	0.0049
South Asian388 / 88,660	0.00448 hom
1KG:XY5 / 2,492	0.002
1KG:XX2 / 2,476	0.00081
Remaining individuals21 / 62,004	0.00034
African/African American1 / 74,948	1.3e-05

0 alternate alleles recorded in 30 other groups: Admixed American, European (Finnish), Middle Eastern, European (non-Finnish), Ashkenazi Jewish, East Asian, Amish, 1KG:ESN, 1KG:PUR, 1KG:PJL, 1KG:CLM, 1KG:JPT, 1KG:CHB, 1KG:TSI, 1KG:MXL, 1KG:CEU, 1KG:MSL, 1KG:YRI, 1KG:FIN, 1KG:KHV, 1KG:CDX, 1KG:LWK, 1KG:ACB, 1KG:ASW, 1KG:IBS, 1KG:GBR, 1KG:PEL, 1KG:GIH, 1KG:CHS, 1KG:GWD.

gnomAD v2.1

AF 0.00056 · 141 / 252,208 alleles · 2 hom · FAF 0.0041

South Asian133 / 27,674	0.00482 hom
Remaining individuals7 / 6,528	0.0011
European (non-Finnish)1 / 114,224	8.8e-06

0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000256186; MAF= 0.02562%, 410/1600398 alleles, homozygotes = 8) and has highest observed frequency in the 1KG:BEB population (AF= 0.020202; MAF= 2.02020%, 4/198 alleles, homozygotes = 0); grpmax FAF= 0.00394201.

gnomAD v2.1

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

For missense variants, BP4 requires HCI prior probability <0.11.

Evidence considered

SpliceAI max delta score 0.01 predicts no significant splice impact

Still missing

HCI prior probability for p.Phe23Leu

Sources

spliceai ↗

Rule

For missense variants, PP3 requires HCI prior probability >0.68; splice-based PP3 applies to non-canonical splice nucleotides with SpliceAI >=0.2.

Evidence considered

SpliceAI max delta score 0.01

Still missing

HCI prior probability for p.Phe23Leu

Sources

spliceai ↗

BP7 N/ANM_000251.3:c.67T>C is a missense variant, not a synonymous or qualifying deep intronic change. Details ▾Hide ▴

Rule

Applies to synonymous or intronic variants at or beyond -21/+7.

Evidence considered

Protein consequence NP_000242.1:p.(Phe23Leu)/p.(F23L)

Sources

prefetch

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 410 / 1,600,398 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB 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

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Likely benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.