Submissions for variant NM_000135.4(FANCA):c.4232C>T (p.Pro1411Leu)

gnomAD frequency: 0.00006  dbSNP: rs201494304

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669832	SCV000794622	uncertain significance	Fanconi anemia complementation group A	2017-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV001246136	SCV001419476	likely benign	Fanconi anemia	2024-01-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000669832	SCV002775467	uncertain significance	Fanconi anemia complementation group A	2022-02-18	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153795	SCV003843746	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155269	SCV003844593	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.4232C>T (p.Pro1411Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251482 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCA causing Fanconi Anemia (9.9e-05 vs 0.0022), allowing no conclusion about variant significance. c.4232C>T has been reported in the literature in an individual affected with breast cancer, without strong evidence for causality (Jalkh_2017), and in a patient with gonadal dysgenesis and microcephaly who was homozgyous for the variant (Mazen_2018). These reports do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. 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: 28202063, 30032139). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pediatrics, Samsung Medical Center, Samsung Medical Center	RCV001252842	SCV001163985	uncertain significance	Microcephaly		no assertion criteria provided	research
Natera, Inc.	RCV001246136	SCV002092469	uncertain significance	Fanconi anemia	2020-02-04	no assertion criteria provided	clinical testing