Classification rationale

BS1 VUS

MSH6 c.942C>G

The MSH6 c.942C>G (p.Ser314Arg) variant has been reported in ClinVar, where most submissions are classified as likely benign or benign, with additional submissions classified as uncertain significance.¹ In gnomAD v4.1, this variant is present at an overall allele frequency of 0.0000223049 (36/1613998 alleles), and the grpmax filtering allele frequency is 0.00027673, which is above the MSH6 BS1 threshold of 0.00022 and below the BA1 threshold of 0.0022.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00; however, no HCI prior probability result was identified to support missense PP3 or BP4 assessment under the MSH6 specification.³

BS1 → VUS

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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_000179.3 · variants mapped to exon structure

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 16 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 · 1

Strength Supporting Moderate Strong Very strong

BS1 strong Benign

This variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.00027673 (0.027673%), which is above the MSH6 BS1 threshold of 0.00022 (0.022%) and below the BA1 threshold of 0.0022 (0.22%); this supports BS1 at Strong strength.

gnomAD v4.1 total AF 2.23049e-05 (36/1613998 alleles)gnomAD v4.1 highest population AF 0.000387121 in African/African American populationgnomAD v4.1 grpmax FAF 0.00027673

gnomad_v4 ↗cspec ↗

Assessed · not applied · 3 not met · 13 not assessed

Pathogenic

PVS1 This variant is a missense substitution, p.(Ser314Arg), and does not fall into the MSH6 PVS1 null-variant categories.

PS1 No VCEP-established pathogenic or likely pathogenic alternate nucleotide change producing the same amino acid substitution was identified, so PS1 cannot be applied.

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

PS3 No variant-specific calibrated functional assay or qualifying mismatch repair defect result was identified for this variant, so PS3 cannot be applied.

PM2 This variant is present in gnomAD v4.1 at an overall allele frequency of 0.0000223049 (36/1613998 alleles), which is above the MSH6 PM2 threshold of less than 0.00002 (<1 in 50,000 alleles); therefore PM2 is not met.

PM3 No data supporting occurrence with another pathogenic MSH6 variant in the constitutional mismatch repair deficiency framework were identified, so PM3 cannot be applied.

PM5 No VCEP-established pathogenic or likely pathogenic missense variant at codon 314 was identified for this review, and PP3 is not met for this variant; therefore PM5 cannot be applied.

PP1 No family segregation data with a calculable Bayes likelihood ratio were identified, so PP1 cannot be applied.

PP3 This is a missense variant.

PP4 No tumor microsatellite instability or mismatch repair immunohistochemistry findings were identified for this case, so PP4 cannot be applied.

Benign

BA1 This variant is present in gnomAD v4.1, but the grpmax filtering allele frequency is 0.00027673 (0.027673%), which is below the MSH6 BA1 threshold of 0.0022 (0.22%); therefore BA1 is not met.

BS2 No confirmed in trans co-occurrence with a known pathogenic MSH6 variant in an individual without evidence of constitutional mismatch repair deficiency was identified, so BS2 cannot be applied.

BS3 No variant-specific calibrated functional assay or qualifying proficient-function result was identified for this variant, so BS3 cannot be applied.

BS4 No segregation dataset showing lack of co-segregation with disease was identified, so BS4 cannot be applied.

BP4 This is a missense variant.

BP5 No tumor profile showing mismatch between the observed tumor findings and MSH6-related disease was identified, so BP5 cannot be applied.

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= 2.23049e-05; MAF= 0.00223%, 36/1613998 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000387121; MAF= 0.03871%, 29/74912 alleles, homozygotes = 0); grpmax FAF= 0.00027673.

v2.1

This variant is present in gnomAD v2.1 (AF= 5.30632e-05; MAF= 0.00531%, 15/282682 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000561167; MAF= 0.05612%, 14/24948 alleles, homozygotes = 0); grpmax FAF= 0.00037952.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0022% · 36 / 1,613,998
0 hom · FAF 0.028%

African/African American 29 / 74,912	0.039%
Remaining individuals 3 / 62,482	0.0048%
Admixed American 1 / 59,990	0.0017%
European (non-Finnish) 3 / 1,180,038	0.00025%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0053% · 15 / 282,682
0 hom · FAF 0.038%

African/African American 14 / 24,948	0.056%
Admixed American 1 / 35,426	0.0028%

+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.188. BayesDel score = -0.304016.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: MSH6, 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; COSV99316054, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Check your email

Reset your password

Enter an access code

Your allowance