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 ↗

Gene diagram · NM_000179.3 · variants mapped to exon structure

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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