Submissions for variant NM_020937.4(FANCM):c.4799C>T (p.Thr1600Ile)

gnomAD frequency: 0.01614  dbSNP: rs61746943

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203014	SCV000258165	benign	not specified	2015-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233839	SCV000290516	benign	Fanconi anemia	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001565172	SCV001788467	likely benign	not provided	2021-01-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000203014	SCV002046772	benign	not specified	2021-03-27	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316124	SCV004015708	benign	Premature ovarian failure 15	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001565172	SCV005211970	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000203014	SCV001549455	benign	not specified		no assertion criteria provided	clinical testing	The FANCM p.Thr1600Ile variant was identified in 20 of 1034 proband chromosomes (frequency: 0.019) from individuals or families with breast or ovarian cancer (Garcia_2009_PMID:19737859; Nguyen-Dumont_2018_PMID:29351780). The variant was identified in dbSNP (ID: rs61746943) and ClinVar (classified as benign by Invitae and Division of Genomic Diagnostics, The Children's Hospital of Philadelphia and as likely benign by Illumina). The variant was identified in control databases in 4968 of 281464 chromosomes (75 homozygous) at a frequency of 0.01765 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: European (Finnish) in 1071 of 25094 chromosomes (freq: 0.04268), European (non-Finnish) in 3124 of 128208 chromosomes (freq: 0.02437), Ashkenazi Jewish in 250 of 10330 chromosomes (freq: 0.0242), Other in 134 of 7176 chromosomes (freq: 0.01867), Latino in 260 of 35298 chromosomes (freq: 0.007366), African in 75 of 24870 chromosomes (freq: 0.003016) and South Asian in 54 of 30558 chromosomes (freq: 0.001767), but was not observed in the East Asian population. The p.Thr1600 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000203014	SCV001798627	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000203014	SCV001806901	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000203014	SCV001964375	benign	not specified		no assertion criteria provided	clinical testing