9-95125148-T-C
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000136.3(FANCC):c.934A>G(p.Ile312Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,614,224 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I312T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000136.3 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCC | NM_000136.3 | c.934A>G | p.Ile312Val | missense_variant | Exon 10 of 15 | ENST00000289081.8 | NP_000127.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FANCC | ENST00000289081.8 | c.934A>G | p.Ile312Val | missense_variant | Exon 10 of 15 | 1 | NM_000136.3 | ENSP00000289081.3 |
Frequencies
GnomAD3 genomes 0.000486 AC: 74AN: 152220Hom.: 1 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000489 AC: 123AN: 251494 AF XY: 0.000449 show subpopulations
GnomAD4 exome AF: 0.000710 AC: 1038AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.000708 AC XY: 515AN XY: 727246 show subpopulations
Age Distribution
GnomAD4 genome 0.000486 AC: 74AN: 152338Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39AN XY: 74484 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:2
Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
This variant is associated with the following publications: (PMID: 26238431, 12670332, 8844212, 26689913, 28767289)
The FANCC p.Ile312Val variant was identified in 1 of 376 proband chromosomes (frequency: 0.003) from individuals with childhood leukemia and was present in 1 of 208 control chromosomes (frequency: 0.005) from healthy individuals (Barber 2003). The variant was also identified in the following databases: dbSNP (ID: rs1800366) as "With Uncertain significance allele", ClinVar (2x uncertain significance, 1x likely benign), Clinvitae (1x uncertain significance, 1x likely benign), and LOVD 3.0 (1x). The variant was not identified in Cosmic or the MutDB, databases. c.934A>G was identified in control databases in 129 of 277246 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 6 of 24038 chromosomes (freq: 0.0003), Other in 3 of 6468 chromosomes (freq: 0.0005), Latino in 16 of 34420 chromosomes (freq: 0.0005), European in 57 of 126728 chromosomes (freq: 0.0005), Finnish in 34 of 25790 chromosomes (freq: 0.001), and South Asian in 13 of 30782 chromosomes (freq: 0.0004). The variant was not observed in the Ashkenazi Jewish or East Asian populations. The p.Ile312 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Fanconi anemia complementation group C Uncertain:4
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
The FANCC c.934A>G (p.Ile312Val) missense change has a maximum founder subpopulation frequency of 0.14% and a maximum non-founder subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has been reported in the heterozygous state an individual with Fanconi anemia and was called a polymorphism (PMID: 8844212). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
not specified Uncertain:1Benign:1
This sequence change does not appear to have been previously described in patients with FANCC-related disorders and has been described in the gnomAD database with a population frequency of 0.049% in the non-Finnish subpopulation (dbSNP rs1800366). The p.Ile312Val change affects a poorly conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile312Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile312Val change remains unknown at this time.
Variant summary: FANCC c.934A>G (p.Ile312Val) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 0.00049 in 251494 control chromosomes (gnomAD v2.1). This frequency is not higher than the maximum estimated for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.0018). However, the variant was reported in some subpopulations with even higher allele frequencies, e.g. in the Amish with an allele frequency of 0.035, including 1 homozygote (gnomAD v4.1). The variant, c.934A>G, has been reported in the literature in heterozygous state as a polymorphism in a patient who was affected with Fanconi Anemia, and was from a consanguineous relationship, thus likely carried an unspecified homozygous pathogenic variant which could explain the phenotype (Gibson_1996). In recent large studies evaluating breast cancer cases and controls the variant was reported with similar or lower frequencies in cases than in controls (Li_2021, and Dorling_2021, reported through LOVD). These results suggest that this variant is not associated with breast cancer risk. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12670332, 33471991, 8844212, 34117267). ClinVar contains an entry for this variant (Variation ID: 127548). Based on the evidence outlined above, the variant was classified as benign.
Fanconi anemia Uncertain:1Benign:1
FANCC-related disorder Uncertain:1
The FANCC c.934A>G variant is predicted to result in the amino acid substitution p.Ile312Val. This variant has been reported in the heterozygous state in an individual with Fanconi anemia (Table 2, Gibson et al. 1996. PubMed ID: 8844212), and in another individual with pancreatic adenocarcinoma (Table A2, Case_12*48, Shindo et al. 2017. PubMed ID: 28767289; eAppendix 1, Table S2, Hu et al. 2020. PubMed ID: 32659497). It has also been reported in 2 individuals with childhood leukemia and in a control cord blood sample (Tables 2 and 3, Barber et al. 2003. PubMed ID: 12670332). This variant is reported in 0.14% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127548/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Hereditary cancer Benign:1
This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at