Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000195976 | SCV000254248 | likely benign | Fanconi anemia | 2024-01-24 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000486496 | SCV000566182 | uncertain significance | not provided | 2023-07-28 | criteria provided, single submitter | clinical testing | Observed in individuals with breast, ovarian, and/or prostate cancer (Lu et al., 2015; Chan et al., 2018); Observed with another FANCC variant in a child with Fanconi anemia, however it is not known whether the variants were on the same or opposite chromosomes (in cis or trans) (Chang et al., 2023); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26689913, 27671336, Gordon2000[Book], 30093976, 36463940) |
Ambry Genetics | RCV001009657 | SCV001169750 | likely benign | Hereditary cancer-predisposing syndrome | 2019-10-23 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Genetic Services Laboratory, |
RCV001818484 | SCV002067705 | uncertain significance | not specified | 2018-12-17 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001354801 | SCV001549502 | likely benign | Fanconi anemia complementation group C | no assertion criteria provided | clinical testing | The FANCC p.Arg334Trp variant was identified in 1 of 356 proband chromosomes (frequency: 0.003) from individuals with prostate adenocarcinoma (Lu 2015). The variant was also identified in dbSNP (ID: rs140348260) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 29 of 273342 chromosomes (1 homozygous) at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 22 of 18788 chromosomes (1 homozygous, freq: 0.001), European in 6 of 124800 chromosomes (freq: 0.00005), and South Asian in 1 of 30446 chromosomes (freq: 0.000033); it was not observed in the African, Other, Latino, Ashkenazi Jewish or Finnish populations. The p.Arg334 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant was identified by our laboratory in a patient with a co-occurring, pathogenic ATM variant (c.1564_1565del, p.Glu522Ilefs*43), increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |