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

gnomAD frequency: 0.00004  dbSNP: rs145466894

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131339	SCV000186313	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	The p.P1579A variant (also known as c.4735C>G), located in coding exon 14 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4735. The proline at codon 1579 is replaced by alanine, an amino acid with highly similar properties. This alteration was functional in a homology directed DNA repair (HDR) assay (Lu C et al. Nat Commun, 2015 Dec;6:10086). Additionally, this variant had 97.71% of wildtype activity in a transcription activation assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1:). 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	RCV000230767	SCV000289810	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 Diagnostics, LLC DBA Color Health	RCV000131339	SCV000906527	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131339	SCV002537777	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588895	SCV004219421	likely benign	not provided	2023-05-03	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.