The MLH1 c.1682A>G (p.Tyr561Cys; p.Y561C) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with uncertain significance submissions.1 This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 3.10936e-06 and grpmax filtering allele frequency 8e-07, which is below the MLH1 PM2_Supporting threshold of 0.00002.2 No variant-specific calibrated functional assay result for this variant was identified in the reviewed MMR functional assay materials, so functional evidence was not used to support or refute pathogenicity.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, and available in silico evidence was insufficient to assign the MLH1 missense PP3 or BP4 rules without an HCI-prior value.4
Final classification
VUS
PM2
MLH1
c.1682A>G
p.Tyr561Cys
This variant
The MLH1 c.1682A>G (p.Tyr561Cys; p.Y561C) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with uncertain significance submissions.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 2.0.0 v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2
VUS
MLH1 c.1682A>G
PM2
→
VUS
3
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
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_000249.4 · variants mapped to exon structure
MLH1
NM_000249.4
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
PM2
supporting
Pathogenic
Population frequency is below the MLH1 PM2_Supporting threshold. In gnomAD v4.1, the total allele frequency is 3.10936e-06 (5/1608050 alleles) with grpmax filtering allele frequency 8e-07, which is below the threshold of 0.00002 (<1 in 50,000 alleles).
gnomAD v4.1 total AF=3.10936e-06 (5/1608050)gnomAD v4.1 grpmax FAF=8e-07gnomAD v2.1 total AF=3.18512e-05 (1/31396)
Assessed · not applied
· 3 not met · 13 not assessed
Pathogenic
PVS1
This variant is a missense substitution, p.Tyr561Cys, and does not fall into the MLH1 PVS1 null-variant categories.
PS1
No previously established MLH1 pathogenic or likely pathogenic variant encoding the same amino acid change by a different nucleotide change was identified in the reviewed VCEP materials, so PS1 was not applied.
PS2
No confirmed de novo occurrence of this variant in an individual with an MLH1-consistent mismatch repair-deficient tumor was identified.
PS3
No variant-specific calibrated functional assay result demonstrating damaging MLH1 function was identified, so PS3 cannot be applied.
PM3
No confirmed in trans observation with another pathogenic or likely pathogenic MLH1 variant in a patient meeting constitutional mismatch repair deficiency criteria was identified.
PM5
No previously established pathogenic or likely pathogenic missense comparator at MLH1 codon 561 was identified in the reviewed VCEP materials, and PP3 was not assigned; therefore PM5 was not applied.
PP1
No segregation data showing co-segregation of this variant with Lynch syndrome-associated disease in affected relatives were identified.
PP3
SpliceAI does not support a splice defect for this variant, with a maximum delta score of 0.01, and the MLH1 PP3 missense rule requires an HCI-prior probability above 0.68 or 0.81, which was not available.
PP4
No tumor microsatellite instability, immunohistochemistry, or MLH1 promoter methylation data were identified to support an MLH1-consistent mismatch repair-deficient phenotype.
Benign
BA1
Population frequency does not meet the MLH1 BA1 threshold.
BS1
Population frequency does not meet the MLH1 BS1 threshold.
BS2
No confirmed observation of this variant in trans with a known pathogenic MLH1 variant in an individual without clinical evidence of constitutional mismatch repair deficiency was identified.
BS3
No variant-specific calibrated functional evidence showing proficient MLH1 function was identified, so BS3 cannot be applied.
BS4
No family segregation study showing lack of co-segregation with Lynch syndrome-associated disease was identified.
BP4
SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, which is below the non-canonical splice threshold of 0.1; however, this is a missense variant, and the MLH1 BP4 missense rule requires an HCI-prior probability below 0.11, which was not available.
BP5
No tumor data showing mismatch repair findings inconsistent with MLH1-associated disease, and no qualifying MLH1 methylation or BRAF V600E evidence, were identified.
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= 3.10936e-06; MAF= 0.00031%, 5/1608050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33701e-05; MAF= 0.00134%, 1/74794 alleles, homozygotes = 0); grpmax FAF= 8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,608,050
0 hom · FAF 8e-05%
0 hom · FAF 8e-05%
African/African American 1 / 74,794 |
0.0013% |
European (non-Finnish) 4 / 1,174,522 |
0.00034% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0032%
· 1 / 31,396
0 hom
0 hom
African/African American 1 / 8,712 |
0.011% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (10 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
Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links