Submissions for variant NM_000135.4(FANCA):c.661A>G (p.Met221Val)

gnomAD frequency: 0.00004  dbSNP: rs150924963

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463486	SCV000547770	uncertain significance	Fanconi anemia	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 221 of the FANCA protein (p.Met221Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with pancreatic cancer (PMID: 15591268). ClinVar contains an entry for this variant (Variation ID: 408195). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCA 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.
Sema4, Sema4	RCV000463486	SCV002535066	uncertain significance	Fanconi anemia	2021-05-10	criteria provided, single submitter	curation
GeneDx	RCV002269275	SCV002552695	uncertain significance	not provided	2022-01-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancreatic cancer (Rogers 2004); This variant is associated with the following publications: (PMID: 15591268)
Fulgent Genetics, Fulgent Genetics	RCV001274656	SCV002778805	uncertain significance	Fanconi anemia complementation group A	2021-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701500	SCV005202837	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.661A>G (p.Met221Val) results in a conservative amino acid change located in the Fanconi anaemia group A protein, N-terminal domain (IPR031729) of 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 3.2e-05 in 249370 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.661A>G has been reported in the literature in an individual affected with Pancreatic cancer (Rogers_2004). These report(s) 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 publication have been ascertained in the context of this evaluation (PMID: 15591268). ClinVar contains an entry for this variant (Variation ID: 408195). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001274656	SCV001459010	uncertain significance	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing