Submissions for variant NM_000135.4(FANCA):c.2859C>G (p.Asp953Glu)

gnomAD frequency: 0.00125  dbSNP: rs149112292

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000431238	SCV000510988	likely benign	not provided	2017-05-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080884	SCV000558886	benign	Fanconi anemia	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001120358	SCV001278839	uncertain significance	Fanconi anemia complementation group A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001120358	SCV001653358	likely benign	Fanconi anemia complementation group A	2021-05-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000431238	SCV002010189	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821151	SCV002065210	likely benign	not specified	2021-06-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001080884	SCV002534974	uncertain significance	Fanconi anemia	2021-10-06	criteria provided, single submitter	curation
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001120358	SCV002757845	uncertain significance	Fanconi anemia complementation group A	2022-06-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000431238	SCV004143603	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	FANCA: BP4
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000431238	SCV004221986	likely benign	not provided	2023-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821151	SCV004241530	likely benign	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.2859C>G (p.Asp953Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00096 in 1613668 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCA causing Fanconi Anemia (0.00096 vs 0.0022), allowing no conclusion about variant significance. c.2859C>G has been reported in the literature in settings of multi-gene panel testing in individuals affected with a personal or family history of breast/ovarian cancer, pancreatic cancer, or inflammatory leiomyosarcoma, reported as a VUS, without evidence for causality (e.g. Bonache_2018, Schwartz_2019, Moradian_2021, Sukhanova_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complementation of cell survival in FANCA-null cells in vitro with MMC treatment at values ~75% of WT (e.g. Kimble_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30306255, 29098742, 23021409, 33558524, 31432501, 35655404). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments, classifying the variant as benign (n=1), likely benign (n=4), uncertain significance (n=4), or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Leiden Open Variation Database	RCV000431238	SCV001425834	pathogenic	not provided	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000431238	SCV001929835	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000431238	SCV001970978	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003902464	SCV004719559	likely benign	FANCA-related disorder	2020-06-26	no assertion criteria provided	clinical testing	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).