NM_000249.4:c.290A>G

MLH1 · NP_000240.1:p.(Tyr97Cys) · NM_000249.4

GRCh37: chr3:37042528 A>G · GRCh38: chr3:37001037 A>G

Gene: MLH1 Transcript: NM_000249.4

Final call

Benign

BA1 stand-alone benign

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.(Tyr97Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The MLH1 c.290A>G (p.Tyr97Cys) variant has been observed once in somatic cancers in COSMIC and has been reported in ClinVar with conflicting germline interpretations, including uncertain significance, likely benign, and benign submissions.

This variant is present in gnomAD at a South Asian grpmax filtering allele frequency of 0.0015372 in v4.1, which is above the MLH1 VCEP BA1 threshold of 0.001; gnomAD v2.1 also shows elevated South Asian frequency with grpmax FAF 0.00153368.

SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01; REVEL is 0.603 and BayesDel is 0.230019, but no MLH1 VCEP HCI prior probability was identified to support PP3 or BP4 for this missense change.

Final determination: Rule17 in the 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 is satisfied by the adjudicated criteria, so the variant is classified as Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
BP6	N/A	This criterion is not used in the MLH1 VCEP framework.	cspec
PS3	Not met	No variant-specific calibrated functional assay result showing a damaging MLH1 effect was identified for this missense variant in the reviewed functional assay documentation or curated evidence sources.	cspec vcep_functional_assay_svi_documentation_mmr oncokb
PM3	Not assessed	No evidence was identified that this variant occurs in trans with a pathogenic or likely pathogenic MLH1 variant in an individual meeting CMMRD-based scoring requirements.	cspec vcep_table_for_cmmrd_diagnosis
PP5	N/A	This criterion is not used in the MLH1 VCEP framework.	cspec
PP4	Not assessed	No tumor microsatellite instability, mismatch repair immunohistochemistry, or MLH1 promoter methylation results were identified, so the Lynch syndrome tumor phenotype requirements for PP4 could not be evaluated.	cspec
BA1	Met	This variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.0015372 in the South Asian population, which is above the MLH1 VCEP BA1 threshold of 0.001. No founder pathogenic designation was identified in the available evidence.	gnomad_v4 clinvar cspec
PS1	Not met	No previously established MLH1 pathogenic or likely pathogenic variant encoding the same Tyr97Cys amino acid change by a different nucleotide change was identified in the reviewed VCEP materials.	cspec vcep_vcep_pilot_variants_mmr
PP2	N/A	This criterion is not applicable in the MLH1 VCEP framework.	cspec
PM5	Not met	No different MLH1 missense variant at Tyr97 established by this VCEP as pathogenic or likely pathogenic on the protein level was identified in the reviewed VCEP materials, so PM5 is not supported.	cspec vcep_vcep_pilot_variants_mmr
PS2	Not assessed	No de novo observation with the required parental confirmation and Lynch syndrome tumor context was identified for this variant.	cspec
BP3	N/A	This criterion is not applicable in the MLH1 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified, so co-segregation with Lynch syndrome-associated disease could not be evaluated.	cspec
BP5	Not assessed	No tumor evidence showing a molecular profile inconsistent with MLH1-related Lynch syndrome, such as MSS tumors, intact relevant MMR protein expression, or MLH1 methylation/BRAF findings, was identified.	cspec
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 0.0015372, which is above the BS1 range of 0.0001 to less than 0.001 and instead falls into the BA1 range.	gnomad_v4 cspec
PVS1	Not met	This variant is a missense change, p.(Tyr97Cys), and does not fall into the default MLH1 null-variant categories for PVS1. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and no RNA evidence showing loss of full-length transcript was identified.	pvs1_gene_context pvs1_variant_assessment cspec spliceai
BP2	N/A	This criterion is not applicable in the MLH1 VCEP framework.	cspec
PM4	N/A	This criterion is not applicable in the MLH1 VCEP framework.	cspec
BP4	Not met	For MLH1 missense variants, BP4 requires an HCI prior probability of pathogenicity below 0.11. No qualifying HCI prior result was identified, and although REVEL is 0.603 and BayesDel is 0.230019, those scores do not substitute for the VCEP missense BP4 rule.	cspec revel bayesdel
PP3	Not met	For MLH1 missense variants, PP3 requires an HCI prior probability of pathogenicity above 0.68. No qualifying HCI prior result was identified, SpliceAI does not support a splice effect with a maximum delta score of 0.01, and the available REVEL and BayesDel scores do not independently satisfy the MLH1 VCEP missense PP3 rule.	cspec spliceai revel bayesdel
BP7	N/A	This variant is a missense substitution rather than a synonymous or qualifying intronic change, so BP7 does not apply.	cspec
PM6	N/A	This criterion is not applicable in the MLH1 VCEP framework.	cspec
PM1	N/A	This criterion is not applicable in the MLH1 VCEP framework.	cspec
BS2	Not assessed	No confirmed in trans co-occurrence with a known pathogenic MLH1 variant in an appropriately phenotyped individual without evidence of CMMRD was identified.	cspec vcep_table_for_cmmrd_diagnosis
BP1	N/A	This criterion is not applicable in the MLH1 VCEP framework.	cspec
BS4	Not assessed	No non-segregation data were identified, so lack of co-segregation with Lynch syndrome-associated disease could not be evaluated.	cspec
BS3	Not met	No variant-specific functional study showing retained MLH1 function or normal RNA behavior was identified for this variant in the reviewed functional assay documentation or curated evidence sources.	cspec vcep_functional_assay_svi_documentation_mmr oncokb
PS4	N/A	This criterion is not used in the MLH1 VCEP framework.	cspec
PM2	Not met	This variant is not absent or extremely rare in gnomAD v4.1. Its total allele frequency is 0.000107785, which is above the MLH1 VCEP PM2 threshold of less than 0.00002.	gnomad_v4 cspec

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