ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4735C>G (p.Pro1579Ala) (rs145466894)

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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 RCV000131339 SCV000186313 uncertain significance Hereditary cancer-predisposing syndrome 2013-08-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000230767 SCV000289810 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 1579 of the BRCA1 protein (p.Pro1579Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs145466894, ExAC 0.01%). This variant has been observed in individuals with ovarian cancer (PMID: 26689913, Invitae). However, in one of these individuals a pathogenic allele was also identified in BRCA1, which suggests that this c.4735C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 142301). An experimental study has shown that this missense change does not impair the homology-directed repair activity of the BRCA1 protein (PMID: 26689913). 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.
GeneDx RCV000588895 SCV000570059 uncertain significance not provided 2016-04-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4735C>G at the cDNA level, p.Pro1579Ala (P1579A) at the protein level, and results in the change of a Proline to an Alanine (CCT>GCT). Using alternate nomenclature, this variant would be defined as BRCA1 4854C>G. This variant was observed in one woman with ovarian cancer whose tumor studies revealed loss of heterozygosity, which suggests this variant may have been involved in tumorigenesis (Lu 2015). BRCA1 Pro1579Ala was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro1579Ala occurs at a position that is not conserved and is located in a region known to interact with multiple proteins (Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro1579Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000855579 SCV000699171 likely benign not specified 2019-04-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4735C>G (p.Pro1579Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246076 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The possibility this variant is a rare polymorphism cannot be excluded. c.4735C>G has been reported in the literature in association with ovarian carcinoma (Lu_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.9253dupA, p.Thr3085fsX26; LabCorp), providing supporting evidence for a benign role. The variant was also reported in the FLOSSIES database in a woman older than age 70 years who never had cancer, providing further supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to have similar activity to the wild-type following assessment via homology-directed repair (HDR) and transcriptional assays (Woods_2016, Lu_2015). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. One ClinVar submission (Invitae) indicates the variant co-occurred with a pathogenic BRCA1, further supporting a benign role. Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000131339 SCV000906527 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000588895 SCV001423215 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 06-21-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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