Submissions for variant NM_001018115.3(FANCD2):c.782A>T (p.Lys261Met)

gnomAD frequency: 0.00001  dbSNP: rs778289599

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002466629	SCV002762345	likely pathogenic	not provided	2022-06-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate exon skipping resulting in a loss of function in a gene for which loss of function is a known mechanism of disease (Kalb et al., 2007); Identified in two unrelated patients with Fanconi anemia who harbor second variants (phase unknown) (Kalb et al., 2007); Also known as p.S232RfsX6; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17436244)
Invitae	RCV002561024	SCV003348655	uncertain significance	Fanconi anemia	2022-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 261 of the FANCD2 protein (p.Lys261Met). This variant is present in population databases (rs778289599, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 17436244). ClinVar contains an entry for this variant (Variation ID: 929646). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002561024	SCV004100067	likely pathogenic	Fanconi anemia	2023-09-21	criteria provided, single submitter	clinical testing	Variant summary: FANCD2 c.782A>T (p.Lys261Met) 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. In addition, this variant disrupts the penultimate nucleotide of exon 10, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site, and one tool predicts the variant weakens the same 5' donor site. Two tools also predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, finding that the variant leads to exon 10 skipping, resulting in a premature termination codon (p.Ser232ArgfsX6; e.g., Kalb_2007). The variant allele was found at a frequency of 1.2e-05 in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.782A>T has been reported in the literature in at least two compound heterozygous individuals affected with Fanconi Anemia (e.g., Kalb_2007). These data indicate that the variant may be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 17436244). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001194907	SCV004196728	likely pathogenic	Fanconi anemia complementation group D2	2023-09-25	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001194907	SCV001364769	pathogenic	Fanconi anemia complementation group D2	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.