MLH1c.1515T>CLikely benign

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Variant interpretation report

MLH1 c.1515T>C, p.(Ser505=)

NM_000249.4:c.1515T>C NP_000240.1:p.(Ser505=) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MLH1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 2 supporting (benign)
Expert rules: ClinGen MLH1 VCEP v2.0.0
Other laboratories (ClinVar): 5 Likely benign · 1 Likely Benign · 1 Benign
Pipeline record: 13 Jul 2026 · version 7.0.3

Evidence considered

View criteria

Applied evidence criteria

BP4 (supporting): VCEP BP4 specifies that for synonymous variants, SpliceAI delta score ≤ 0.1 qualifies as BP4_supporting. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with a synonymous variant that does not alter splicing.
BP7 (supporting): VCEP BP7 applies to synonymous (silent) variants at or beyond -21/+7 from exonic splice boundaries. NM_000249.4:c.1515T>C (p.Ser505=) is a synonymous variant located at position +105 from the exon 13 donor splice site and -43 from the exon 13 acceptor splice site, both well beyond the -21/+7 splice consensus boundaries. This deep exonic synonymous substitution is unlikely to affect splicing.

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 MLH1 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: 2

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2

BP4Supporting

BP4 · supporting

VCEP BP4 specifies that for synonymous variants, SpliceAI delta score ≤ 0.1 qualifies as BP4_supporting. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with a synonymous variant that does not alter splicing.

BP7Supporting

BP7 · supporting

VCEP BP7 applies to synonymous (silent) variants at or beyond -21/+7 from exonic splice boundaries. NM_000249.4:c.1515T>C (p.Ser505=) is a synonymous variant located at position +105 from the exon 13 donor splice site and -43 from the exon 13 acceptor splice site, both well beyond the -21/+7 splice consensus boundaries. This deep exonic synonymous substitution is unlikely to affect splicing.

Recorded classification: Likely benign

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: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.

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

5 / 1,614,044 alleles

gnomAD v4.1: 5 / 1,614,044 alleles. Recorded AF 3.09781e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.98829e-05; MAF= 0.00199%, 5/251472 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000217462; MAF= 0.02175%, 4/18394 alleles, homozygotes = 0); grpmax FAF= 7.353e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

7 reported laboratory submissions

5 Likely benign · 1 Likely Benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen MLH1 VCEP v2.0.0, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 12 not met · 0 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

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

Met Not met Not assessed Not applicable

NM_000249.4:c.1515T>C is a synonymous variant (p.Ser505=) in MLH1 exon 13, located well beyond splice consensus boundaries at c.1515 (+105 from donor, -43 from acceptor).

SpliceAI predicts no splicing impact for this variant (max delta score = 0.00), meeting BP4_supporting under the InSiGHT MLH1 VCEP specification.

The variant meets BP7_supporting as a synonymous substitution at or beyond -21/+7 from exonic splice boundaries, where it is unlikely to alter splicing.

The variant is present in gnomAD v4.1 at low frequency (grpmax FAF = 2.978e-05; 5/1,614,044 alleles) but does not meet PM2_supporting (threshold <0.00002) or BS1 (threshold ≥0.0001).

No functional data, tumor pathology data, co-segregation data, de novo observations, or variant-specific literature were identified for this variant.

This variant has been reported in ClinVar as Likely benign by 7 clinical laboratories (ClinVar Variation ID: 413362).

Under the InSiGHT MLH1 VCEP v2.0.0 combining rules, two supporting benign criteria (BP4 + BP7) yield a classification of Likely Benign (Rule 19: ≥2 Benign Supporting).

Met · 2

BP4 SupportingVCEP BP4 specifies that for synonymous variants, SpliceAI delta score ≤ 0.1 qualifies as BP4_supporting. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with a synonymous variant that does not alter splicing. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 for NM_000249.4:c.1515T>C
synonymous variant with no predicted splice impact

Sources

spliceai ↗

BP7 SupportingVCEP BP7 applies to synonymous (silent) variants at or beyond -21/+7 from exonic splice boundaries. NM_000249.4:c.1515T>C (p.Ser505=) is a synonymous variant located at position +105 from the exon 13 donor splice site and -43 from the exon 13 acceptor splice site, both well beyond the -21/+7 splice consensus boundaries. This deep exonic synonymous substitution is unlikely to affect splicing. Details ▾Hide ▴

Evidence considered

Synonymous variant p.(Ser505=) at c.1515 in exon 13
position +105 from donor
-43 from acceptor
beyond -21/+7 boundaries

Not met · 12 · evaluated, threshold not reached

PS2 No de novo observations have been reported for this variant. No evidence of de novo occurrence was identified in ClinVar submissions, publications, or other sources. Details ▾Hide ▴

Still missing

No de novo testing or family studies available

PS3 No functional data are available for this synonymous variant (p.Ser505=). The variant was not directly tested in any calibrated MMR functional assay. The VCEP functional assay spreadsheet does not include data for this variant, and OncoKB lists Unknown Oncogenic Effect with no associated PMIDs. Details ▾Hide ▴

Still missing

No functional assay data available for this synonymous variant

PM2 VCEP PM2 rule requires gnomAD v4 grpmax filtering allele frequency < 0.00002 (<1 in 50,000 alleles). The observed gnomAD v4 grpmax FAF is 2.978e-05 (0.00002978), which exceeds the 0.00002 threshold. The variant is present in 5/1,614,044 alleles in gnomAD v4.1 and 5/251,472 alleles in gnomAD v2.1. Does not meet the PM2_supporting frequency criterion. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 2.978e-05 exceeds VCEP PM2 threshold of <0.00002

Sources

gnomad_v4 ↗

PP1 No co-segregation data are available for this variant. No pedigrees or family studies were identified in the evidence sources. Details ▾Hide ▴

Still missing

No co-segregation or pedigree data available

PP3 VCEP PP3 requires HCI prior probability >0.68 (missense) or SpliceAI delta ≥ 0.2 for non-canonical splice sites. HCI prior was not found for this variant. SpliceAI max delta score is 0.00, well below the 0.2 threshold. No evidence supports a damaging effect from in silico predictions. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no predicted splice impact)
HCI prior not available for c.1515T>C

Sources

spliceai ↗

PP4 No tumor data demonstrating MSI-H status or loss of MMR protein expression consistent with the variant location are available for this variant. Details ▾Hide ▴

Still missing

No tumor MSI/IHC data available

BA1 VCEP BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.001 (0.1%). The observed gnomAD v4 grpmax FAF is 2.978e-05, far below the 0.1% threshold. BA1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 2.978e-05 is well below BA1 threshold of 0.001

Sources

gnomad_v4 ↗

BS1 VCEP BS1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0001 and < 0.001 (0.01-0.1%). The observed gnomAD v4 grpmax FAF is 2.978e-05, which is below the lower threshold of 0.0001. BS1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 2.978e-05 is below BS1 lower threshold of 0.0001

Sources

gnomad_v4 ↗

BS2 No evidence of co-occurrence in trans with a known pathogenic variant in a patient with CRC after age 45 without clinical manifestations of CMMRD. No phase-confirmed observations available. Details ▾Hide ▴

Still missing

No trans co-occurrence data available

BS3 No functional studies demonstrating a benign effect are available for this variant. The variant has not been evaluated in any calibrated MMR functional assay or other functional system. Details ▾Hide ▴

Still missing

No functional assay data available

BS4 No lack-of-segregation data are available for this variant. No pedigrees demonstrating non-segregation with disease were identified. Details ▾Hide ▴

Still missing

No segregation data available

BP5 No tumor data demonstrating MSS status or absence of MMR protein expression loss are available for this variant. BP5 requires multiple tumors with MSS and/or no loss of MMR protein expression. Details ▾Hide ▴

Still missing

No tumor MSS/IHC data available

Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ASynonymous variant encoding p.(Ser505=) with no predicted effect on protein sequence. PVS1 is reserved for null variants (nonsense, frameshift, canonical splice, initiation codon) and does not apply to synonymous substitutions under the MLH1 VCEP framework. Details ▾Hide ▴