Submissions for variant NM_001018115.3(FANCD2):c.2965C>G (p.Pro989Ala)

gnomAD frequency: 0.00003  dbSNP: rs200568638

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823688	SCV000964556	uncertain significance	Fanconi anemia	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 989 of the FANCD2 protein (p.Pro989Ala). This variant is present in population databases (rs200568638, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FANCD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134320). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FANCD2 protein function. 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.
Illumina Laboratory Services, Illumina	RCV001145539	SCV001306227	uncertain significance	Fanconi anemia complementation group D2	2018-01-13	criteria provided, single submitter	clinical testing	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.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000120994	SCV001984607	uncertain significance	not specified	2020-11-22	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237726	SCV002011300	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001145539	SCV002779439	uncertain significance	Fanconi anemia complementation group D2	2024-01-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407514	SCV004113991	uncertain significance	FANCD2-related disorder	2023-07-05	criteria provided, single submitter	clinical testing	The FANCD2 c.2965C>G variant is predicted to result in the amino acid substitution p.Pro989Ala. To our knowledge, this variant has not been reported in the literature in individuals with FANCD2-related disorders. This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-10119870-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ITMI	RCV000120994	SCV000085162	not provided	not specified	2013-09-19	no assertion provided	reference population