Submissions for variant NM_000135.4(FANCA):c.3412C>G (p.Leu1138Val)

gnomAD frequency: 0.00041  dbSNP: rs138417003

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000228134	SCV000283562	benign	Fanconi anemia	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000674808	SCV000399826	likely benign	Fanconi anemia complementation group A	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Counsyl	RCV000674808	SCV000800208	likely benign	Fanconi anemia complementation group A	2018-05-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001311466	SCV001501639	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	FANCA: BS2
Genetic Services Laboratory, University of Chicago	RCV000120938	SCV002068419	likely benign	not specified	2018-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120938	SCV002500151	benign	not specified	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.3412C>G (p.Leu1138Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251228 control chromosomes, predominantly at a frequency of 0.0093 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000228134	SCV002535004	likely benign	Fanconi anemia	2021-07-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000674808	SCV002804219	likely benign	Fanconi anemia complementation group A	2022-05-04	criteria provided, single submitter	clinical testing
ITMI	RCV000120938	SCV000085106	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000674808	SCV001462878	benign	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120938	SCV001552187	benign	not specified		no assertion criteria provided	clinical testing	The FANCA p.Leu1138Val variant was identified in 1 of 90 proband chromosomes (frequency: 0.011) from individuals with breast cancer (Jalkh_2017_PMID:28202063). The variant was identified in dbSNP (ID: rs138417003) and ClinVar (classified as benign by Invitae, as likely benign by Counsyl and as uncertain significance by Illumina). The variant was identified in control databases in 390 of 282634 chromosomes (5 homozygous) at a frequency of 0.00138 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 284 of 30614 chromosomes (freq: 0.009277), Other in 13 of 7222 chromosomes (freq: 0.0018), Latino in 30 of 35420 chromosomes (freq: 0.000847), African in 18 of 24960 chromosomes (freq: 0.000721) and European (non-Finnish) in 45 of 129076 chromosomes (freq: 0.000349), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Leu1138 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.