About FH
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FH c.6C>T, p.(Tyr2=)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000143.4:c.6C>T is present in gnomAD at very low overall allele frequency: 0.025% in v2.1 (45/178374 alleles, grpmax FAF 0.018%) and 0.013% in v4.1 (199/1544456 alleles, grpmax FAF 0.029%). Both overall AF and grpmax FAF are below the 0.1% threshold. No homozygotes observed. Not detected in gnomAD-Canada. Caveat: Ashkenazi Jewish subpopulation AF is 0.33% (v2.1) / 0.30% (v4.1), exceeding the 0.1% cutoff, but the controlling grpmax FAF remains below threshold.
Benign criteria applied · 1
BP6Supporting
BP6 · supporting
Multiple reputable clinical laboratories have independently classified NM_000143.4:c.6C>T as benign or likely benign in ClinVar (4 labs Benign, 6 labs Likely benign; 9 usable submissions with criteria provided). While the specific evidence supporting their classifications is not publicly available for independent evaluation, the consensus among established clinical testing laboratories meets BP6 at supporting benign strength.
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: PM2 supporting, BP6 supporting; combination = 1 supporting + 1 supporting benign, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
199 / 1,544,456 alleles
gnomAD v4.1: 199 / 1,544,456 alleles. Recorded AF 0.000128848. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000252279; MAF= 0.02523%, 45/178374 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00329334; MAF= 0.32933%, 28/8502 alleles, homozygotes = 0); grpmax FAF= 0.00017843.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
10 reported laboratory submissions
6 Likely benign · 4 Benign.
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
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.
Met
Not met
Not assessed
Not applicable
NM_000143.4:c.6C>T is a synonymous variant (p.Tyr2=) in exon 1 of FH, which encodes fumarate hydratase. This variant is present in gnomAD at low overall frequency: 0.025% in v2.1 (45/178,374 alleles) and 0.013% in v4.1 (199/1,544,456 alleles), with grpmax filtering allele fractions of 0.018% and 0.029% respectively, meeting PM2 at supporting strength.
The variant has been classified as Benign or Likely benign by multiple reputable clinical laboratories in ClinVar (Variation ID 184570): 4 laboratories classify as Benign and 6 as Likely benign, with criteria provided. The consensus among established clinical testing laboratories meets BP6 at supporting benign strength.
SpliceAI predicts no splicing impact (max delta score 0.00), and the variant does not lie within a known mutational hotspot or the fumarate lyase domain. No functional studies, cosegregation data, de novo reports, or case-control analyses are available for this variant.
PVS1, PS1, PS5, PM5, PP2, BP1, BP3, PM3, and PM4 are not applicable to this synonymous variant. The remaining pathogenic criteria (PS2, PS3, PS4, PM1, PM6, PP1, PP3, PP4, PP5) are not met. All benign criteria except BP6 are not met or not assessed. BA1 and BS1 are not met as the overall allele frequency is below respective thresholds.
The net evidence tally consists of one supporting pathogenic criterion (PM2_supporting) and one supporting benign criterion (BP6_supporting). Under ACMG/AMP 2015 combination rules (PMID:25741868), when benign and pathogenic criteria cancel at the supporting level, the variant defaults to Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_000143.4:c.6C>T is present in gnomAD at very low overall allele frequency: 0.025% in v2.1 (45/178374 alleles, grpmax FAF 0.018%) and 0.013% in v4.1 (199/1544456 alleles, grpmax FAF 0.029%). Both overall AF and grpmax FAF are below the 0.1% threshold. No homozygotes observed. Not detected in gnomAD-Canada. Caveat: Ashkenazi Jewish subpopulation AF is 0.33% (v2.1) / 0.30% (v4.1), exceeding the 0.1% cutoff, but the controlling grpmax FAF remains below threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF 0.025% (grpmax FAF 0.018%)
- gnomAD v4.1 AF 0.013% (grpmax FAF 0.029%)
- gnomAD-Canada: absent
- No homozygotes in any population database
Still missing
- ASJ subpopulation AF exceeds PM2 threshold
- consider whether population-specific cutoffs should be applied
Sources
BP6 SupportingMultiple reputable clinical laboratories have independently classified NM_000143.4:c.6C>T as benign or likely benign in ClinVar (4 labs Benign, 6 labs Likely benign; 9 usable submissions with criteria provided). While the specific evidence supporting their classifications is not publicly available for independent evaluation, the consensus among established clinical testing laboratories meets BP6 at supporting benign strength. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 labs classify as Benign
- 6 labs as Likely benign
- 9 of 11 submissions are usable for classification
- Submitters include Invitae/Labcorp
- GeneDx
- Ambry Genetics
- Quest Diagnostics
- PreventionGenetics
Still missing
- Specific internal evidence from submitters not publicly available
Sources
Not met · 17 · evaluated, threshold not reached
PS2 No de novo occurrence of NM_000143.4:c.6C>T has been reported in the literature or ClinVar submissions; exploratory literature search found no de novo reports. Details ▾Hide ▴
Evidence considered
- No de novo reports identified
Still missing
- No de novo data available
PS3 No well-established in vitro or in vivo functional studies have been identified for NM_000143.4:c.6C>T. REVEL and BayesDel do not score synonymous variants. No published functional assays assessing splicing, enzyme activity, or protein expression for this variant. Details ▾Hide ▴
Evidence considered
- No functional evidence in ClinVar or published literature
- SpliceAI predicts no splice impact (delta 0.00) but this is in silico only
Still missing
- No functional studies available for this synonymous variant
Sources
PS4 No published case-control studies compare the prevalence of NM_000143.4:c.6C>T in FH-related disease (HLRCC) patients versus controls. Population frequency in gnomAD alone does not satisfy PS4 without statistical enrichment analysis in affected individuals. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 45/178374 alleles (0.025%)
- gnomAD v4.1: 199/1544456 alleles (0.013%)
- No case-control enrichment data
Still missing
- No case-control studies comparing variant prevalence in HLRCC patients vs. controls
Sources
PM1 NM_000143.4:c.6C>T resides in exon 1 (residue Tyr2), outside the fumarate lyase domain (exons 5-7) that harbors established mutational hotspots for FH in HLRCC. No clustering of pathogenic variants at this residue has been reported. Details ▾Hide ▴
Evidence considered
- Variant lies outside the lyase domain (mutational hotspot in exons 5-7)
- Not identified as a statistically significant hotspot residue
PM6 No de novo reports for NM_000143.4:c.6C>T; no maternity/paternity confirmation data available. Exploratory literature search found no de novo observations. Details ▾Hide ▴
Evidence considered
- No de novo reports identified
Still missing
- No de novo data available
PP1 No cosegregation studies have been published for NM_000143.4:c.6C>T in affected families. Exploratory search found no segregation data. Details ▾Hide ▴
Evidence considered
- No cosegregation data available
Still missing
- No family cosegregation studies
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL and BayesDel do not score synonymous variants (both returned not found). SpliceAI predicts no splicing impact (max delta 0.00). No HCI prior score available for FH. No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: not applicable to synonymous variant
- BayesDel: not applicable to synonymous variant
- SpliceAI max delta score 0.00 (no splice impact)
- HCI prior: gene not supported
Still missing
- Missense-oriented in silico tools not applicable to synonymous variants
Sources
PP4 No detailed phenotypic data available for patients carrying NM_000143.4:c.6C>T. The variant's phenotype specificity or family history cannot be assessed from available sources. Details ▾Hide ▴
Evidence considered
- ClinVar submissions lack detailed phenotype information
Still missing
- No phenotype or family history data available for assessment
Sources
PP5 PP5 requires a reputable source to report the variant as pathogenic with evidence unavailable for independent evaluation. ClinVar reports NM_000143.4:c.6C>T as Likely benign (6 clinical laboratories) and Benign (4 clinical laboratories). No reputable source reports it as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Likely benign (6 labs) and Benign (4 labs)
- No reputable source reports as pathogenic
Sources
BA1 NM_000143.4:c.6C>T overall allele frequency in gnomAD is 0.025% (v2.1) and 0.013% (v4.1), both well below the 1% BA1 threshold. Not applicable as a stand-alone benign criterion. Details ▾Hide ▴
BS1 NM_000143.4:c.6C>T overall allele frequency in gnomAD is 0.025% (v2.1, grpmax FAF 0.018%) and 0.013% (v4.1, grpmax FAF 0.029%), both below the 0.3% BS1 threshold. The Ashkenazi Jewish subpopulation AF is elevated at 0.33% (v2.1) / 0.30% (v4.1), but the controlling grpmax FAF remains below threshold for a dominant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF 0.025% (grpmax FAF 0.018%)
- gnomAD v4.1 overall AF 0.013% (grpmax FAF 0.029%)
- ASJ subpopulation AF 0.30-0.33% marginally exceeds threshold but grpmax FAF controls
Still missing
- ASJ subpopulation frequency (0.33%) marginally exceeds BS1 threshold
- may warrant population-specific benign weight in ASJ-ancestry patients
Sources
BS2 The variant is observed in heterozygous state in gnomAD population databases (45-199 alleles). However, BS2 requires observation in a healthy adult individual for a disorder with complete penetrance expected at an early age. HLRCC has variable penetrance and later onset; gnomAD observation alone does not satisfy BS2. For the recessive FH deficiency context, no homozygotes are observed. Details ▾Hide ▴
Evidence considered
- gnomAD: observed in heterozygous state only
- no homozygotes
- HLRCC has incomplete penetrance and adult onset
Still missing
- Cannot confirm healthy status of gnomAD carriers
- HLRCC penetrance is not complete at early age
Sources
BS3 No well-characterized functional studies demonstrate a neutral effect for NM_000143.4:c.6C>T. No in vitro or in vivo assays assessing splicing, enzyme activity, or protein expression exist for this variant. The SpliceAI prediction (delta 0.00) is in silico only and does not constitute a functional study. Details ▾Hide ▴
Evidence considered
- No functional studies identified
- SpliceAI delta 0.00 is in silico only
- not functional evidence
Still missing
- No functional studies demonstrating neutral effect
Sources
BS4 No cosegregation data demonstrating non-segregation of NM_000143.4:c.6C>T with disease in affected families. Exploratory search found no relevant family studies. Details ▾Hide ▴
Evidence considered
- No non-segregation data available
Still missing
- No family cosegregation or non-segregation data
BP2 No published instance of a healthy individual carrying NM_000143.4:c.6C>T in trans with a known pathogenic FH variant. gnomAD shows no homozygotes, and no compound heterozygous reports exist for FH deficiency cases. Details ▾Hide ▴
Evidence considered
- No documented trans configuration with pathogenic FH allele
- No homozygotes in gnomAD
- no compound heterozygote reports
Still missing
- No trans-configuration data available
Sources
BP4 Multiple lines of computational evidence are insufficient to support no impact. REVEL and BayesDel are not designed for synonymous variants (both returned not found). SpliceAI predicts no splicing impact (delta 0.00), but this single line of in silico evidence does not meet the 'multiple lines' requirement for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI delta 0.00 suggests no splice impact
- REVEL/BayesDel unavailable for synonymous variants
Still missing
- Conservation data not available
- Single in silico line insufficient for BP4 'multiple lines' requirement
Sources
BP5 No cases have been reported where NM_000143.4:c.6C>T was found in a patient with an alternate molecular basis for disease. No such data available in ClinVar or published literature. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available
Still missing
- No data on co-occurrence with alternate molecular diagnoses
Not assessed · 1 · no assessment recorded
BP7 BP7 requires both (a) splicing prediction algorithms predict no impact to splice consensus or creation of new splice site, AND (b) the nucleotide is not highly conserved. SpliceAI delta 0.00 satisfies condition (a), but nucleotide-level conservation data for position c.6 in FH exon 1 is not available. Cannot fully assess BP7 without conservation information. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00: no splice impact predicted
- Conservation data unavailable for c.6 position
Still missing
- Nucleotide conservation data for c.6 position needed to complete BP7 assessment
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000143.4:c.6C>T is a synonymous substitution encoding p.Tyr2= (no amino acid change) and does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus) defined for PVS1 per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Synonymous variant with no predicted null effect
- SpliceAI max delta 0.00 confirms no cryptic splice alteration
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 applies when the same amino acid change has been previously established as pathogenic regardless of nucleotide change. NM_000143.4:c.6C>T is a synonymous variant (p.Tyr2=) with no amino acid change; therefore PS1 does not apply. Details ▾Hide ▴
Evidence considered
- Synonymous variant produces no amino acid change
PM3 N/ASkipped per user directive — trivially not applicable. Details ▾Hide ▴
Evidence considered
- Skipped per user directive
PM4 N/ASkipped per user directive — trivially not applicable. Details ▾Hide ▴
Evidence considered
- Skipped per user directive
PM5 N/APM5 requires a different missense change at the same amino acid residue as an established pathogenic missense variant. NM_000143.4:c.6C>T is a synonymous variant (p.Tyr2=) with no amino acid change and no residue context suitable for classic PM5 semantics. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no amino acid residue change
- Unable to confirm classic same-residue PM5 semantics
Sources
pm5_candidates
PP2 N/APP2 is defined for missense variants in genes where missense variants are a common mechanism of disease and benign missense variation is rare. NM_000143.4:c.6C>T is a synonymous variant, not a missense variant; PP2 does not apply. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- not missense
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. NM_000143.4:c.6C>T is a synonymous variant, not a missense variant; BP1 does not apply. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- not missense
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. Not applicable to a single-nucleotide synonymous substitution. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame indel
PS5 N/APS5 requires a novel missense change at an amino acid residue where a different missense change has been established as pathogenic. NM_000143.4:c.6C>T is a synonymous variant with no amino acid change, and no pathogenic missense variant has been established at codon 2 (Tyr2). Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no amino acid change
- No known pathogenic missense at Tyr2
Identifiers
- Gene
- FH
- Transcript
- NM_000143.4
- Coding (HGVS c.)
- NM_000143.4:c.6C>T
- Protein (HGVS p.)
- NP_000134.2:p.(Tyr2=)
- GRCh38
- chr1:241519717 G>A
- GRCh37
- chr1:241683017 G>A
- ClinVar
- 184570
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FH
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
199 / 1,544,456 alleles
AF 0.000129 · 0 homozygotes · FAF 0.000288
gnomAD v2.1
45 / 178,374 alleles
AF 0.000252 · 0 homozygotes · FAF 0.000178
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00013 · 199 / 1,544,456 alleles · 0 hom · FAF 0.00029
| Ashkenazi Jewish85 / 28,504 | 0.003 |
| Middle Eastern2 / 4,578 | 0.00044 |
| South Asian33 / 83,580 | 0.00039 |
| Remaining individuals19 / 59,670 | 0.00032 |
| East Asian6 / 40,706 | 0.00015 |
| European (Finnish)7 / 59,102 | 0.00012 |
| European (non-Finnish)46 / 1,143,940 | 4e-05 |
| Admixed American1 / 50,768 | 2e-05 |
0 alternate alleles recorded in 2 other groups: Amish, African/African American.
gnomAD v2.1
AF 0.00025 · 45 / 178,374 alleles · 0 hom · FAF 0.00018
| Ashkenazi Jewish28 / 8,502 | 0.0033 |
| Remaining individuals2 / 5,282 | 0.00038 |
| South Asian8 / 22,282 | 0.00036 |
| East Asian3 / 12,262 | 0.00024 |
| European (Finnish)1 / 18,642 | 5.4e-05 |
| European (non-Finnish)3 / 70,378 | 4.3e-05 |
0 alternate alleles recorded in 2 other groups: African/African American, Admixed American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000128848; MAF= 0.01288%, 199/1544456 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00298204; MAF= 0.29820%, 85/28504 alleles, homozygotes = 0); grpmax FAF= 0.00028848.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000252279; MAF= 0.02523%, 45/178374 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00329334; MAF= 0.32933%, 28/8502 alleles, homozygotes = 0); grpmax FAF= 0.00017843.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL and BayesDel do not score synonymous variants (both returned not found). SpliceAI predicts no splicing impact (max delta 0.00). No HCI prior score available for FH. No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: not applicable to synonymous variant
- BayesDel: not applicable to synonymous variant
- SpliceAI max delta score 0.00 (no splice impact)
- HCI prior: gene not supported
Still missing
- Missense-oriented in silico tools not applicable to synonymous variants
Sources
BP4 Multiple lines of computational evidence are insufficient to support no impact. REVEL and BayesDel are not designed for synonymous variants (both returned not found). SpliceAI predicts no splicing impact (delta 0.00), but this single line of in silico evidence does not meet the 'multiple lines' requirement for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI delta 0.00 suggests no splice impact
- REVEL/BayesDel unavailable for synonymous variants
Still missing
- Conservation data not available
- Single in silico line insufficient for BP4 'multiple lines' requirement
Sources
BP7 BP7 requires both (a) splicing prediction algorithms predict no impact to splice consensus or creation of new splice site, AND (b) the nucleotide is not highly conserved. SpliceAI delta 0.00 satisfies condition (a), but nucleotide-level conservation data for position c.6 in FH exon 1 is not available. Cannot fully assess BP7 without conservation information. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00: no splice impact predicted
- Conservation data unavailable for c.6 position
Still missing
- Nucleotide conservation data for c.6 position needed to complete BP7 assessment
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP consensus guideline for sequence variant interpretation. A methodological framework paper that does not assess or report any specific FH variants, including NM_000143.4:c.6C>T.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016Describes a standardized DNA variant scoring system for Mendelian disorder pathogenicity assessment. A methodological paper that does not mention NM_000143.4:c.6C>T or any specific FH variant.Does not name this variant
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PMID 20301430 ↗FH Tumor Predisposition Syndrome.Adam MP et al. · 1993GeneReviews overview of FH Tumor Predisposition Syndrome (HLRCC). Discusses FH gene and associated clinical phenotypes at the syndrome level but does not enumerate or evaluate NM_000143.4:c.6C>T.Does not name this variant
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PMID 24319509 ↗Canadian guideline on genetic screening for hereditary renal cell cancers.Reaume MN et al. · 2013Canadian guideline on genetic screening for hereditary renal cell cancers. Discusses FH as an HLRCC-associated gene at the syndrome level but does not enumerate or assess specific FH variants, including NM_000143.4:c.6C>T.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline for cancer predisposition assessment referral indications. A clinical practice guideline that does not mention specific FH variants.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ summary on cancer genetics risk assessment and counseling. A broad overview document that does not mention specific FH variants.Does not name this variant
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PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ summary on genetics of skin cancer. A broad overview document without specific FH variant content.Does not name this variant
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PMID 26389510 ↗Genetics of Renal Cell Carcinoma (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ summary on genetics of renal cell carcinoma. Discusses FH in the context of HLRCC at the syndrome level but does not mention NM_000143.4:c.6C>T.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc refinement of ACMG-AMP variant classification criteria. A methodological framework paper that does not assess or report any specific FH variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
199 / 1,544,456 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
6 Likely benign · 4 Benign
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/184570/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-241683017-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-241519717-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-241519717-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000143.4%3Ac.6C%3…
- OncoKB ↗www.oncokb.org/gene/FH/Y2=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FH+c.6C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000128848; MAF= 0.01288%, 199/1544456 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00298204; MAF= 0.29820%, 85/28504 alleles, homozygotes = 0); grpmax FAF= 0.00028848.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000252279; MAF= 0.02523%, 45/178374 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00329334; MAF= 0.32933%, 28/8502 alleles, homozygotes = 0); grpmax FAF= 0.00017843.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (4 clinical laboratories). (ClinVarID = 184570)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.