0%
FHc.364_367delUncertain significance
Print report
Variant interpretation report

FH c.364_367del, p.(Lys122GlnfsTer5)

NM_000143.4:c.364_367del NP_000134.2:p.(Lys122GlnfsTer5) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About FH

No gene-level summary was recorded for this case.

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 Not recorded. 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_000143.4:c.364_367del is a 4-base pair deletion in exon 3 of 10 that creates a frameshift and premature termination codon (p.Lys122GlnfsTer5) at amino acid 126 of 510, predicted to trigger nonsense-mediated decay. FH loss of function is an established disease mechanism for hereditary leiomyomatosis and renal cell cancer (HLRCC), supported by extensive germline literature. Under ClinGen SVI PVS1 recommendations (PMC6185798), a frameshift variant predicted to undergo NMD in a gene where LoF is the established mechanism qualifies for PVS1 at full strength.

PM2Supporting
PM2 · supporting

NM_000143.4:c.364_367del is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), representing a total of over 250,000 alleles screened without observation. Under generic ACMG/AMP 2015 rules for non-VCEP genes, absence from large population databases at an allele frequency below 0.1% qualifies for PM2 at supporting strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.

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 Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 17 not met · 1 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000143.4:c.364_367del is a 4-base pair deletion in exon 3 of FH that creates a frameshift and premature termination at codon 126 (p.Lys122GlnfsTer5), predicted to undergo nonsense-mediated decay and result in complete loss of fumarate hydratase function.

FH loss of function is an established disease mechanism for autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC), supported by extensive germline literature demonstrating that protein-truncating FH mutations cause MCUL/HLRCC through a classic two-hit tumor suppressor mechanism.

The variant is absent from large population databases including gnomAD v2.1 and v4.1, with zero alleles observed across over 250,000 screened individuals.

Under the generic ACMG/AMP 2015 framework, this variant meets PVS1 at very_strong strength (null variant in a gene where LoF is a known disease mechanism) and PM2 at supporting strength (absent from population databases). Per the ACMG combination rules, one very_strong criterion with one supporting criterion is most consistent with a Likely Pathogenic classification. Although the strict ACMG 2015 combination table requires two supporting criteria or one moderate criterion with PVS1 for a Pathogenic classification, the totality of evidence — a definitive null variant in a well-established tumor suppressor gene, completely absent from population databases — supports a Likely Pathogenic designation with a recommendation to consider upgrading to Pathogenic if additional evidence (e.g., patient phenotype consistent with HLRCC, segregation data, or functional confirmation) becomes available.

Met · 2

PVS1 Very strongNM_000143.4:c.364_367del is a 4-base pair deletion in exon 3 of 10 that creates a frameshift and premature termination codon (p.Lys122GlnfsTer5) at amino acid 126 of 510, predicted to trigger nonsense-mediated decay. FH loss of function is an established disease mechanism for hereditary leiomyomatosis and renal cell cancer (HLRCC), supported by extensive germline literature. Under ClinGen SVI PVS1 recommendations (PMC6185798), a frameshift variant predicted to undergo NMD in a gene where LoF is the established mechanism qualifies for PVS1 at full strength. Details ▾Hide ▴
Evidence considered
  • 4-bp frameshift deletion in exon 3/10
  • premature stop at codon 126
  • NMD predicted (truncation >75% of protein
  • upstream of last exon)
  • FH LoF established as germline disease mechanism for HLRCC/MCUL
  • MANE Select transcript (NM_000143.4)
Sources
pvs1_generic_framework ↗gnomad_v2 ↗gnomad_v4 ↗
PM2 SupportingNM_000143.4:c.364_367del is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), representing a total of over 250,000 alleles screened without observation. Under generic ACMG/AMP 2015 rules for non-VCEP genes, absence from large population databases at an allele frequency below 0.1% qualifies for PM2 at supporting strength. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 17 · evaluated, threshold not reached

PS2 No de novo data were identified for this variant in the reviewed literature or ClinVar submissions. De novo confirmation requires direct observation of the variant in an affected proband with confirmed parental absence. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PS3 No variant-specific functional data were identified for NM_000143.4:c.364_367del. The reviewed literature (Tomlinson 2002, Alam 2003) describes general FH functional assays and enzyme activity measurements for other FH mutations, but neither paper tested this specific variant. No systematic range characterization (saturation mutagenesis or tiling screen) covering codon 122 was identified. The OncoKB annotation of Likely Loss-of-function is a curated knowledge base inference, not primary functional evidence for PS3. Details ▾Hide ▴
Evidence considered
  • FH LoF mechanism established at gene level (Tomlinson 2002
  • Alam 2003)
  • OncoKB curated annotation: Likely Oncogenic
  • Likely Loss-of-function (not primary functional data)
Still missing
  • No variant-specific functional assay data available
  • No systematic mutational range characterization covering codon 122
PS4 No variant-specific prevalence or case-control data were identified. The variant is absent from ClinVar and was not reported in any of the four reviewed publications. PS4 requires a statistically significant enrichment of the variant in affected individuals versus controls. Details ▾Hide ▴
Still missing
  • No case-control or prevalence data available
PM1 The variant is not located in a statistically significant mutational hotspot (cancerhotspots.org negative). While the frameshift truncation removes the FH fumarate lyase catalytic domain and active site, this loss of critical functional domains is already captured by PVS1 at very_strong strength for this null variant. Applying PM1 in addition would constitute double-counting the same domain-level evidence. No independent residue-specific hotspot or domain-based criterion independent of the null effect is met. Details ▾Hide ▴
Evidence considered
  • Not in a statistically significant cancer hotspot
  • Domain-level truncation captured by PVS1
PM6 No de novo observation was identified for this variant in the reviewed literature or databases. PM6 requires a confirmed de novo event with both maternity and paternity confirmed. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PP1 No segregation data are available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • No segregation data available
PP3 SpliceAI predicts no significant splice impact (max delta score 0.02). REVEL and BayesDel scores are unavailable as they are not applicable to frameshift variants. No in silico tools support a deleterious effect for this variant type beyond what PVS1 already captures. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.02 (no predicted splice impact)
  • REVEL/BayesDel not applicable to deletions
Sources
spliceai ↗
PP5 This variant is absent from ClinVar. No reputable source has classified this variant. PP5 requires a pathogenic or likely pathogenic classification from a ClinVar submitter with at least 3-star expert panel review status. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0. BA1 requires an allele frequency above 1% in population databases. This variant does not meet the BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0 in gnomAD (far below 1% BA1 threshold)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD v2.1 and v4.1. BS1 requires an allele frequency above 0.3% in population databases under the generic ACMG framework. This variant has an allele frequency of 0 and does not meet the BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0 in gnomAD (far below 0.3% BS1 threshold)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available regarding observation of this variant in healthy adult individuals. BS2 requires observation of the variant in a healthy adult for a disorder with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
  • No data on observation in healthy controls
BS3 No functional studies demonstrate a benign effect for this variant. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. Details ▾Hide ▴
Still missing
  • No functional studies performed on this variant
BS4 No segregation data are available. BS4 requires lack of segregation of the variant with disease in affected family members. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
  • No phase data available
BP4 SpliceAI predicts no significant splice impact (max delta 0.02), but this is a protein-truncating frameshift variant whose pathogenicity is mediated at the protein level, not through splicing. REVEL and BayesDel scores are unavailable as they do not apply to frameshift variants. No in silico evidence supports a benign interpretation specific to this variant type that would contradict the null effect predicted by PVS1. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.02 (no splice effect predicted
  • but splice is not the pathogenic mechanism for this variant)
Sources
spliceai ↗
BP5 No data are available suggesting an alternative molecular basis for disease in a case where this variant was observed. BP5 requires observation of the variant in a case with an alternate molecular cause. Details ▾Hide ▴
Still missing
  • No alternate cause data available
BP6 This variant is absent from ClinVar. BP6 requires a benign or likely benign classification from a ClinVar submitter with at least 3-star expert panel review status. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

PP4 No patient-specific phenotype data are available for this variant assessment. PP4 requires that the affected individual's phenotype or family history is highly specific for the disease associated with FH (HLRCC/MCUL: multiple cutaneous leiomyomata, uterine fibroids, and/or renal cell carcinoma). Details ▾Hide ▴
Still missing
  • Patient phenotype and clinical history not provided
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is defined for missense variants where a different nucleotide change produces the same amino acid change as an established pathogenic variant. This variant is a frameshift deletion; PS1 semantics do not apply. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per instruction. FH-associated HLRCC/MCUL is autosomal dominant; PM3 applies to recessive disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 is intended for non-null variants (in-frame deletions/insertions, stop-loss) that alter protein length without triggering NMD. This variant is a frameshift deletion predicted to undergo NMD and is already captured by PVS1 at very_strong strength. Under PMC6185798, PM4 should not be stacked with PVS1 for the same null variant. Details ▾Hide ▴
Sources
pvs1_generic_framework ↗
PM5 N/APM5 requires a different missense change at the same amino acid residue as an established pathogenic missense variant. This variant is a frameshift deletion; no same-residue missense comparator semantics can be established. PM5 candidate harvesting confirmed no eligible comparators. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 is defined for missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is a frameshift deletion, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where only truncating variants are a known cause of disease. This variant is itself a truncating (frameshift) variant, so BP1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 is defined for in-frame deletions or insertions in repetitive regions without a known function. This variant is a frameshift deletion, not an in-frame variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 is defined for synonymous (silent) variants with no predicted splice impact. This variant is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 defines a relationship between an established pathogenic missense variant and a different missense change at the same residue. This variant is a 4-bp frameshift deletion, not a missense variant. The same-residue comparator semantics do not apply. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
FH
Transcript
NM_000143.4
Coding (HGVS c.)
NM_000143.4:c.364_367del
Protein (HGVS p.)
NP_000134.2:p.(Lys122GlnfsTer5)
GRCh38
chr1:241513613 GCCTT>G
GRCh37
chr1:241676913 GCCTT>G

Gene diagram

Every interpreted variant in FH, mapped onto the exon structure of NM_000143.4. Select a row to find it on the plot.

FHNM_000143.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +93 bp
0.000
SpliceAI acceptor gainat +67 bp
0.000
SpliceAI donor lossat -10 bp
0.000
SpliceAI donor gainat -17 bp
0.020
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts no significant splice impact (max delta score 0.02). REVEL and BayesDel scores are unavailable as they are not applicable to frameshift variants. No in silico tools support a deleterious effect for this variant type beyond what PVS1 already captures. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.02 (no predicted splice impact)
  • REVEL/BayesDel not applicable to deletions
Sources
spliceai ↗
BP4 SpliceAI predicts no significant splice impact (max delta 0.02), but this is a protein-truncating frameshift variant whose pathogenicity is mediated at the protein level, not through splicing. REVEL and BayesDel scores are unavailable as they do not apply to frameshift variants. No in silico evidence supports a benign interpretation specific to this variant type that would contradict the null effect predicted by PVS1. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.02 (no splice effect predicted
  • but splice is not the pathogenic mechanism for this variant)
Sources
spliceai ↗
BP7 N/ABP7 is defined for synonymous (silent) variants with no predicted splice impact. This variant is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

4 paper records listed. 2 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
    Describes the discovery that germline FH mutations cause multiple cutaneous and uterine leiomyomatosis and papillary renal cell cancer. Reports 25 mutations (truncating, missense, in-frame deletion) in 42 probands, demonstrating that FH acts as a tumor suppressor with loss of the wild-type allele in tumors and reduced fumarate hydratase enzyme activity in affected individuals. NM_000143.4:c.364_367del was not among the reported mutations.
    → PVS1 Does not name this variant
    PMID 11865300 ↗
    Source detail
    We found mutations in FH in 25 of the 42 probands analyzed (Table 1), including protein-truncating mutations, the two large germline deletions, missense changes and an in-frame deletion.

    Location Table 1 lists all 24 specific mutations (none match); Results section describes mutation spectrum and functional enzyme assays in lymphoblastoid cells and tumors.

    Context Lymphoblastoid cell line fumarate hydratase activity assays; tumor LOH analysis by microsatellite markers

  • Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.
    Reports additional FH mutations in MCUL and fumarate hydratase deficiency patients. Characterizes 20 distinct germline mutations in 35 of 46 MCUL probands, maps them onto the FH crystal structure, and demonstrates that protein-truncating FH mutations are functionally null alleles. NM_000143.4:c.364_367del was not among the reported mutations.
    → PVS1 Does not name this variant
    PMID 12761039 ↗
    Source detail
    Protein-truncating FH mutations are functionally null alleles.

    Location Table 1 lists all 20 mutations (none match); Results section 'Mutations in MCUL patients' describes mutation types and functional characterization.

    Context Lymphoblastoid cell line fumarase activity assays; western blotting for protein stability; structural modeling onto E. coli fumarase C crystal structure

Other recorded publications

  • Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
    Screens North American families with HLRCC for FH mutations and confirms FH as the susceptibility gene. Reports germline FH mutations in affected families. NM_000143.4:c.364_367del was not identified in the abstract of this paper.
    Does not name this variant
    PMID 12772087 ↗
  • Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.
    Characterizes clinical and genetic features of 21 new HLRCC families including the first two African-American families, identifies novel FH mutations, and expands the phenotypic spectrum. NM_000143.4:c.364_367del was not identified in the abstract of this paper.
    Does not name this variant
    PMID 15937070 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.