Submissions for variant NM_007294.4(BRCA1):c.425C>A (p.Pro142His)

gnomAD frequency: 0.00004  dbSNP: rs55971303

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112613	SCV000244358	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	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 = 0.00000103
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079537	SCV000076518	benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000259147	SCV000209908	benign	not specified	2017-07-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000162718	SCV000213180	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000034749	SCV000231725	uncertain significance	not provided	2014-09-04	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112613	SCV000267680	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034749	SCV000699126	likely benign	not provided	2016-03-16	criteria provided, single submitter	clinical testing	Variant summary: The c.425C>A variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to His. 3/4 in-silico tools predict this variant to be damaging. This variant was found in 7/122892 control chromosomes from the large and broad populations from ExAC at a frequency of 0.000057, which is lower that the maximal expected frequency of a pathogenic allele (0.0010005) in this gene. The variant has been reported in multiple patients with breast and/or ovarian cancer without strong evidence for causality. The variant is found to co-occur with other deleterious variants in BRCA1/2 including its presence in trans with a known pathogenic variant BRCA1 187delAG aka c.68_69delAG (Judkins_2005/BIC) and BRCA2 c.5576_5579delTTAA (UMD), a very strong evidence that the variant should be benign. Although drug sensitivity, E2 interaction, and homology-directed recombination (HDR) assays were normal, single-strand annealing (SSA) was impaired (Bouwman_2013,Towler_2013, Wei_2008, Morris_2006). Multiple clinical laboratories as well as reputable databases have classified this variant as benign/likely benign. Multifactorial probability based model also shows the variant to be benign (Lindor_2012, Easton_2007). Taken together, this variant has been classified as Likely Benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034749	SCV000883460	likely benign	not provided	2017-11-06	criteria provided, single submitter	clinical testing	The BRCA1 c.425C>A; p.Pro142His variant is published in the medical literature as having a low probability of pathogenicity (Chenevix-Trench 2006, Lindor 2012). The variant is listed in the ClinVar database (Variation ID: 41823) as benign or likely benign by the majority of submitters. The variant is listed in the dbSNP variant database (rs55971303) and in the Genome Aggregation Database in 25/276378 alleles. The proline at this position is moderately conserved across species, with at least one mammal with a serine at this position. Additionally, functional studies show this variant can function as the wild type protein (Bouwman 2013). Considering available information, this variant is classified as likely benign. References: Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 2013 Oct;3(10):1142-55. Chenevix-Trench G et al. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res. 2006 Feb 15;66(4):2019-27. Lindor NM et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 Jan;33(1):8-21.
Color Diagnostics, LLC DBA Color Health	RCV000162718	SCV000910791	benign	Hereditary cancer-predisposing syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162718	SCV002538280	likely benign	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	curation
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034749	SCV000043188	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112613	SCV000145455	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112613	SCV000297609	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2006-06-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353863	SCV000591265	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Pro142His variant was identified in 7 of 7460 proband chromosomes (frequency 0.001) from individuals with breast or ovarian cancer (Borg 2010, Caux-Moncoutier 2011, Tazzite 2012, Uhrhammer 2008) and was absent in 360 control chromosomes from healthy individuals (Chenevix-Trench 2006). The variant was also identified in the following databases: dbSNP (ID: rs55971303) as "With other allele", ClinVar (classified as benign by ENIGMA, Invitae, GeneDx, Ambry Genetics, SCRP; as likely benign by COGR, Michigan Medical Genetics Laboratories, University of Michigan, Integrated Genetics/Laboratory Corporation of America; as uncertain significance by BIC, and two clinical laboratories), COGR , LOVD 3.0 (11x), UMD-LSDB (7x as neutral), BIC Database (12x unknown significance), and in ARUP Laboratories (not pathogenic or of no clinical significance). The variant was not identified in Cosmic, MutDB, and Zhejiang University database. The variant was identified with a co-occurring pathogenic BRCA2 variant (c.5576_5579delTTAA, p.Ile1859LysfsX3) in UMD and in trans with a known deleterious mutation, BRCA1 c.68delAG (alias: BIC 187delAG) (Judkins 2005), increasing the likelihood that the p.Pro142His variant does not have clinical significance. The variant was identified in control databases in 25 of 276378 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6438 chromosomes (freq: 0.0003), Latino in 9 of 34258 chromosomes (freq: 0.0003), European in 14 of 126510 chromosomes (freq: 0.0001), but not in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. One functional study found that the variant abolished association of BRCA1 with Ku80 protein and failed to restore resistance to ionizing irradiation in BRCA1-deficient cells, which the authors suggested may lead to a classification of likely pathogenic (Wei 2008). However, the p.Pro142His variant was predicted neutral by in silico studies using either hierarchical or multi-factorial likelihood models (Capanu 2011, Easton 2007, Lindor 2012), and one loss-of-heterozygosity study demonstrated loss of the variant in a tumor, which further suggests that this variant is neutral (Chenevix-Trench 2006). Functional assays to assess DNA repair by both homology directed recombination (HDR) and single strand annealing (SSA) found the variant to be HDR proficient, suggesting the variant was neutral (Towler 2013). In contrast the variant was identified by sequencing in an Italian male breast cancer patient, for which the variant was confirmed to segregate with the disease in four affected family members, however four additional family members were positive for the variant and unaffected including a 41 year old male and a 88 year old male (Spinelli 2015). The p.Pro142 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact 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 (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.