NM_001127500.3:c.110T>C

MET · NP_001120972.1:p.(Val37Ala) · NM_001127500.3

GRCh37: chr7:116339248 T>C · GRCh38: chr7:116699194 T>C

Gene: MET Transcript: NM_001127500.3

Final call

Likely Benign

BS1 strong BP4 supporting

Variant details

Gene

MET

Transcript

NM_001127500.3

Protein

NP_001120972.1:p.(Val37Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The MET c.110T>C (p.Val37Ala) variant has been reported in ClinVar with likely benign and benign submissions.

This variant is present in population databases at a frequency above the BS1 threshold, with the highest observed frequency of 0.70588% in South Asian individuals in gnomAD v2.1 and 0.68732% in South Asian individuals in gnomAD v4.1, arguing against a rare pathogenic germline variant.

No well-established variant-specific functional study was identified to support either a damaging or a normal effect.

Computational evidence supports a benign interpretation, with SpliceAI predicting no significant splice impact (maximum delta score 0.00), REVEL of 0.142, and BayesDel of -0.247812.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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
PVS1	N/A	This variant is a missense substitution, p.(Val37Ala), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1 or 2 splice variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No reviewed evidence was identified showing that a different nucleotide change produces the same amino acid substitution with an established pathogenic classification.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified parentage was identified for this variant.
PS3	Not assessed	No well-established functional study demonstrating a damaging effect of this specific variant was identified.	oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals compared with population databases. The variant is present in ClinVar, but no case-control or multiple affected-case data supporting significant excess were identified.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant is not supported to lie in a well-established mutational hotspot or critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at codon 37.	hotspots oncokb
PM2	Not met	Population frequency is not low enough for PM2. In gnomAD v2.1 the highest subpopulation frequency is 0.70588% in South Asian individuals, and in gnomAD v4.1 the highest subpopulation frequency is 0.68732% in South Asian individuals, both above the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	No evidence relevant to trans occurrence in a recessive disease context was identified for this variant.
PM4	N/A	This variant is a missense substitution and does not change protein length or create an in-frame insertion or deletion.
PM5	N/A	Classic same-residue PM5 comparator logic could not be confirmed for this case, and no reviewed pathogenic same-residue comparator variant was identified.	pm5_candidates
PM6	Not assessed	No presumed de novo occurrence without confirmed parentage was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	Available evidence does not establish that this gene has a low rate of benign missense variation and that missense variation is the predominant mechanism required for PP2 application in this case.
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.142, and BayesDel is -0.247812.	spliceai revel bayesdel
PP4	Not assessed	No phenotype-specific evidence was provided to show that the clinical presentation is highly specific for a disorder caused by this gene.
PP5	N/A	This criterion was not used because external assertions without primary supporting evidence are not applied here.	clinvar
BA1	Not met	Population frequency does not reach the 1% BA1 threshold. The highest observed subpopulation frequency is 0.70588% in gnomAD v2.1 South Asian and 0.68732% in gnomAD v4.1 South Asian.	gnomad_v2 gnomad_v4
BS1	Met	Population frequency is above the 0.3% BS1 threshold. The highest observed frequency is 0.70588% in gnomAD v2.1 South Asian individuals and 0.68732% in gnomAD v4.1 South Asian individuals, which argues against a rare pathogenic germline variant.	gnomad_v2 gnomad_v4
BS2	Not assessed	Although this variant is observed in population databases, the available evidence was not sufficient to apply BS2 on the basis of observation in unaffected individuals alone.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating normal function of this specific variant was identified.	oncokb
BS4	Not assessed	No family data were identified showing lack of segregation of this variant with disease.
BP1	N/A	BP1 was not applied because the required pattern of disease being caused primarily by truncating variants was not established for this case.
BP2	Not assessed	No phase information was identified to show this variant occurring in trans with a pathogenic variant or in cis with another variant in a way that supports BP2.
BP3	N/A	This variant is not an in-frame insertion or deletion in a repetitive region.
BP4	Met	Multiple computational results support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.142, and BayesDel is -0.247812, which together support a benign computational interpretation.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular diagnosis or other established cause of disease was provided that would support BP5.
BP6	N/A	This criterion was not used because external assertions without accessible supporting evidence are not applied here.	clinvar
BP7	N/A	This variant is not a synonymous or deep intronic change, so BP7 does not apply.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.