Submissions for variant NM_000465.4(BARD1):c.1361C>T (p.Pro454Leu)

dbSNP: rs772285343

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222233	SCV000276145	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	clinical testing	The p.P454L variant (also known as c.1361C>T), located in coding exon 5 of the BARD1 gene, results from a C to T substitution at nucleotide position 1361. The proline at codon 454 is replaced by leucine, an amino acid with similar properties. This variant was reported in 1/255 ovarian cancer patients but was not observed in 1000 unselected population-based controls or 200 healthy, age-matched, female controls. Using RNA extracted from this patient's serous ovarian tumor, mRNA expression analysis showed an in-frame deletion of exon 5 (Ratajska M et al. Oncol. Rep., 2015 Nov;34:2609-17). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however direct evidence is insufficient at this time (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration as a missense substitution is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000587485	SCV000568444	uncertain significance	not provided	2023-07-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A functional study demonstrated through mRNA analysis that this variant results in in-frame skipping of exon 5 (Ratajska et al., 2015); Observed in individuals with ovarian or breast cancer as well as at least one unaffected individual in a breast cancer case-control study (Ratajska et al., 2015; Dorling et al., 2021; Suszynska et al., 2022); This variant is associated with the following publications: (PMID: 26329992, 33471991, 37418175, 18480049, 34906988, 32726901, 35650591)
Color Diagnostics, LLC DBA Color Health	RCV000222233	SCV000688116	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587485	SCV000696740	uncertain significance	not provided	2016-06-27	criteria provided, single submitter	clinical testing	Variant summary: The BARD1 c.1361C>T (p.Pro454Leu) variant involves the alteration of a conserved nucleotide. This variant is located within the ANK repeats of the protein which suggest possible alteration of the BARD1 structure and/or interactions with other proteins. 4/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant causes a loss of binding motif for splicing enhancer SC15. This variant was found in 1/121022 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188). This variant has been reported in one OvC patient and was shown to cause exon 5 skipping resulting in-frame deletion from c.1315 to c.1395 [r.(=,1315_1395del);p.Gly439_Leu465del], and this this deletion results in disruption of the 1st and 2nd ANK repeat (Ratajska_Oncol Rep_2015). In addition, one clinical diagnostic laboratory classified this variant as VUS, without evidence to independently evaluate. Taken together, because of the absence of clinical information and the lack of functional studies, the variant was classified as VUS-possibly pathogenic until more evidence becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054172	SCV001218475	uncertain significance	Familial cancer of breast	2023-05-25	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 232097). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26329992). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 454 of the BARD1 protein (p.Pro454Leu). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. Studies have shown that this missense change is associated with altered splicing resulting in in-frame skipping of exon 5 (PMID: 26329992).
Sema4, Sema4	RCV000222233	SCV002527005	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	curation
Baylor Genetics	RCV001054172	SCV004214981	uncertain significance	Familial cancer of breast	2023-10-02	criteria provided, single submitter	clinical testing