NM_000143.4:c.143delA

FH · NP_000134.2:p.(Asn48IlefsTer5) · NM_000143.4

GRCh37: chr1:241680605 AT>A · GRCh38: chr1:241517305 AT>A

Gene: FH Transcript: NM_000143.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

Transcript

NM_000143.4

Protein

NP_000134.2:p.(Asn48IlefsTer5)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The FH c.143del (p.(Asn48IlefsTer5), p.(N48Ifs*5)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the 0.1% rarity threshold used for PM2 in non-VCEP interpretation.

The variant is predicted to cause an early truncating frameshift in FH, and FH loss of function is an established germline disease mechanism, supporting PVS1 under the generic ClinGen SVI PVS1 framework; SpliceAI predicts no significant splice impact with a max delta score of 0.00.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	This variant is a frameshift change in FH, NM_000143.4:c.143del, predicted to cause p.(Asn48IlefsTer5) / p.(N48Ifs*5). FH loss of function is an established germline disease mechanism, and this early truncating variant occurs in exon 2 with a predicted premature stop far upstream of the 3' end, supporting application of PVS1 under the generic ClinGen SVI PVS1 framework.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is not applicable because this is a frameshift variant rather than a different nucleotide change producing the same amino acid substitution as a known pathogenic variant.	pvs1_variant_assessment
PS2	Not assessed	No confirmed de novo occurrence with parental relationship confirmation was identified for this variant.
PS3	Not assessed	Variant-specific well-established functional studies were not identified. Available FH publications and curated literature links support the gene-disease mechanism, but they do not provide sufficient directly reviewed functional evidence for this exact variant to apply PS3.	oncokb PMID:11865300 PMID:12761039 PMID:12772087 PMID:15937070
PS4	Not assessed	No case-control enrichment data or count of unrelated affected individuals with this exact variant was identified, so PS4 cannot be assessed from the available evidence.	clinvar
PM1	Not met	This variant has not been shown to occur in a well-established mutational hotspot or a critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 rarity threshold of 0.1%, supporting PM2 at supporting strength.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applied because this review is using generic ACMG criteria for FH tumor predisposition, where pathogenicity is not being established through recessive trans observations.	pvs1_gene_context
PM4	N/A	PM4 is not applied because this protein-length-changing variant is already a predicted loss-of-function frameshift for which PVS1 is the more appropriate criterion.	pvs1_variant_assessment
PM5	N/A	PM5 is not applicable because this is not a missense change, and the available PM5 review could not support classic same-residue missense comparator logic for this variant.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.
PP1	Not assessed	No segregation data were identified for this exact variant, so PP1 cannot be applied.
PP2	N/A	PP2 is not applicable because this variant is not a missense change.	pvs1_variant_assessment
PP3	N/A	PP3 is not applied because this is a frameshift variant rather than a missense or splice-region variant requiring computational pathogenicity support. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but that does not add independent pathogenic evidence beyond the predicted truncating consequence.	spliceai pvs1_variant_assessment
PP4	Not assessed	No individual-level phenotype, tumor profile, or family history was provided that would allow assessment of whether the presentation is highly specific for an FH-related disorder.
PP5	Not assessed	No reputable source assertion with sufficient exact-variant classification detail was identified for criterion use.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the benign stand-alone frequency threshold of 1.0%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the benign strong frequency threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a context sufficient to apply BS2.
BS3	Not assessed	Variant-specific well-established functional studies showing no damaging effect were not identified, so BS3 cannot be applied.	oncokb PMID:11865300 PMID:12761039 PMID:12772087 PMID:15937070
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	N/A	BP1 is not applicable because this is not a missense variant in a gene where truncating variants are not known to cause disease; here the variant is a truncating frameshift in a gene with loss-of-function disease mechanism.	pvs1_gene_context pvs1_variant_assessment
BP2	Not assessed	No phase data with another variant were identified, so BP2 cannot be assessed.
BP3	Not assessed	No evidence was identified that this variant lies in a repetitive region or a region without known function that would support BP3.
BP4	N/A	BP4 is not applied because this is a frameshift variant rather than a missense or synonymous variant suitable for benign computational prediction criteria. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but that does not provide standalone benign evidence against the predicted truncating effect.	spliceai pvs1_variant_assessment
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided that would support BP5.
BP6	Not assessed	No reputable source benign assertion for this exact variant was identified.	clinvar
BP7	N/A	BP7 is not applicable because this is not a synonymous or intronic variant.	pvs1_variant_assessment

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