Submissions for variant NM_007294.4(BRCA1):c.2180C>T (p.Pro727Leu)

gnomAD frequency: 0.00001  dbSNP: rs80356912

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077509	SCV001161493	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000167
Ambry Genetics	RCV000215724	SCV000275645	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	The p.P727L variant (also known as c.2180C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2180. The proline at codon 727 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual with a personal and family history of pancreatic cancer and in an Italian patient who underwent BRCA1/2 gene sequencing (Ghiorzo P et al. J. Med. Genet. 2012 Mar;49(3):164-70; Zanella I et al. Exp Mol Pathol. 2017 Apr;102(2):314-320). This variant was also reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Analysis of conservation in multiple mammalian species indicates that this position is not fixed and is, therefore, less likely to be functionally important (Burk-Herrick A et al. Mamm. Genome 2006 Mar;17(3):257-70). This alteration was also classified as benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This amino acid position is poorly 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.
GeneDx	RCV000350348	SCV000329125	likely benign	not provided	2019-04-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16518693, 22368299, 26727311, 28263838)
Color Diagnostics, LLC DBA Color Health	RCV000215724	SCV000912042	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 727 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000188) and in an individual affected with pancreatic cancer (PMID: 22368299). A multifactorial analysis has reported likelihood ratios for pathogenicity based on segregation and tumor pathology of 0.0628 and 0.13, respectively (PMID: 31131967). This variant has been identified in 3/250472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000350348	SCV001133516	uncertain significance	not provided	2018-11-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174871	SCV001338266	uncertain significance	not specified	2020-02-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2180C>T (p.Pro727Leu) 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. In addition, at least two papers report that this variant was classified as non-pathogenic based on segregation analysis alone or multifactorial likelihood analysis incorporating segregation, pathology, and other data points (Flower_2015, Padilla_2019). The variant allele was found at a frequency of 1.2e-05 in 250472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2180C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer and pancreatic cancer (Shattuck-Eidens_1997, Gorringe_2008, Ghiorzo_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001323203	SCV001514109	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077509	SCV000109309	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-02-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077509	SCV000144320	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1997-11-14	no assertion criteria provided	clinical testing