rs540805431
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 5P and 3B. PM2PM5PP3BP4_ModerateBP6
The NM_001018115.3(FANCD2):āc.2273G>Cā(p.Cys758Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,598,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. C758Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001018115.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCD2 | NM_001018115.3 | c.2273G>C | p.Cys758Ser | missense_variant | 25/44 | ENST00000675286.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCD2 | ENST00000675286.1 | c.2273G>C | p.Cys758Ser | missense_variant | 25/44 | NM_001018115.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000388 AC: 59AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000530 AC: 133AN: 251082Hom.: 1 AF XY: 0.000457 AC XY: 62AN XY: 135698
GnomAD4 exome AF: 0.000184 AC: 266AN: 1446424Hom.: 1 Cov.: 29 AF XY: 0.000160 AC XY: 115AN XY: 720758
GnomAD4 genome ? AF: 0.000387 AC: 59AN: 152274Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38AN XY: 74442
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 04, 2021 | This sequence change has been previously described in a patient cohort with head and neck squamous cell carcinoma (HNSCC); no other details were provided (PMID: 28678401). This sequence change has been described in the gnomAD database with a relatively higher population frequency of 0.33% in the Latino subpoulation (dbSNP rs540805431). The p.Cys758Ser change affects a highly conserved amino acid residue located in a domain of the FANCD2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys758Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Cys758Ser change remains unknown at this time. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2022 | Variant summary: FANCD2 c.2273G>C (p.Cys758Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251082 control chromosomes, predominantly at a frequency of 0.0033 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6.82 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCD2 causing Fanconi Anemia phenotype (0.00048), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.2273G>C has been reported in the literature in settings of multigene panel testing for head and neck squamous cell carcinoma (HNSCC) and breast cancer without strong evidence for causality (example Chandrasekharappa_2017, Bonache_2018). To our knowledge no individuals with the variant affected with Fanconi Anemia and no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Fanconi anemia Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 09, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Fanconi anemia complementation group D2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 05, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2022 | Identified in an individual with head and neck squamous cell carcinoma and in a cohort of probands from families with high breast cancer risk, however, detailed clinical information was not provided (Chandrasekharappa et al., 2017; Bonache et al., 2018); Identified as heterozygous in a patient with hepatoblastoma, multiple congenital anomalies, and developmental delay. Patient also reported to have multiple additional variants in known/candidate cancer predisposition genes (Aguiar et al., 2022).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28678401, 30306255, 35495172) - |
Hepatoblastoma Uncertain:1
Uncertain significance, no assertion criteria provided | research | Molecular Oncology - Human Genetics Lab, University of Sao Paulo | - | - - |
FANCD2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 13, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at