ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.73G>C (p.Ala25Pro) (rs751646468)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164946 SCV000215635 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-08 criteria provided, single submitter clinical testing The p.A25P variant (also known as c.73G>C), located in coding exon 1 of the BARD1 gene, results from a G to C substitution at nucleotide position 73. The alanine at codon 25 is replaced by proline, an amino acid with highly similar properties. This alteration was reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet. 2016 Jun;53:366-76). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000203712 SCV000260135 uncertain significance Familial cancer of breast 2020-10-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 25 of the BARD1 protein (p.Ala25Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 185506). This variant has been reported not to substantially affect BARD1 protein function (PMID: 31371347). 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.
Fulgent Genetics,Fulgent Genetics RCV000203712 SCV000896922 uncertain significance Familial cancer of breast 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164946 SCV000910929 likely benign Hereditary cancer-predisposing syndrome 2016-03-03 criteria provided, single submitter clinical testing
Cancer Genetics Service,National Cancer Centre Singapore RCV000203712 SCV000920886 uncertain significance Familial cancer of breast 2019-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354641 SCV001549305 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 p.Ala25Pro variant was not identified in the literature. The variant was identified in dbSNP (ID: rs751646468) “With Uncertain significance allele”, and ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was identified in control databases in 9 of 258670 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 2 of 21472 chromosomes (freq: 0.00009) and East Asian in 7 of 18300 chromosomes (freq: 0.0004), while not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Ala25 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Pro 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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