Starting

Initialising…

FANCL

Final classification

VUS

FANCL c.233C>G · p.Pro78Arg

FANCL

Gene

FANCL

Transcript

NM_018062.3

HGVS · transcript:coding

NM_018062.3:c.233C>G

Consequence

N/A

GRCh38

chr2:58226768 G>C

GRCh37

chr2:58453903 G>C

Basis 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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS. ▾

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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

Classification rationale

PM2 BP4 VUS

FANCL c.233C>G

This missense variant (c.233C>G, p.Pro78Arg) in FANCL is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=0.000496%, 8/1,612,860 alleles, no homozygotes), meeting PM2 at supporting strength.¹ Multiple lines of computational evidence (REVEL 0.105, BayesDel -0.364706, SpliceAI max delta 0.04) suggest no damaging impact on the gene product, meeting BP4 at supporting benign strength.² This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories with no expert panel classification; no case-control, functional, or segregation data specific to this variant were identified.³ With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and the variant is classified as Uncertain significance per ACMG/AMP 2015 combination rules (PMID:25741868).⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_018062.3 · variants mapped to exon structure

FANCL NM_018062.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 4.96013e-06; MAF= 0.00050%, 8/1612860 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00016469; MAF= 0.01647%, 1/6072 alleles, homozygotes = 0); grpmax FAF= 1.065e-05.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0005% · 8 / 1,612,860
0 hom · FAF 0.0011%

Middle Eastern 1 / 6,072	0.016%
Remaining individuals 3 / 62,454	0.0048%
African/African American 3 / 74,796	0.004%
European (non-Finnish) 1 / 1,179,488	8.5e-05%

+ 6 not observed (Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 2199165)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.105. BayesDel score = -0.364706.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

18197057 ↗ Carrier screening in individuals of Ashkenazi Jewish descent. CLINVAR

19888064 ↗ ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. CLINVAR

20301575 ↗ Fanconi Anemia. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389333 ↗ Genetics of Skin Cancer (PDQ®): Health Professional Version. CLINVAR