17-43104138-G-T

Variant names:

• chr17-43104138-G-T
• rs55971303
• NM_007294.4:c.425C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):​c.425C>A​(p.Pro142His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P142T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:11
• Conservation: PhyloP100: 0.639
• Publications: 26 publications found

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15402275).
• BP6: Variant 17-43104138-G-T is Benign according to our data. Variant chr17-43104138-G-T is described in ClinVar as Benign. ClinVar VariationId is 41823.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.425C>A	p.Pro142His	missense	Exon 6 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.425C>A	p.Pro142His	missense	Exon 6 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.425C>A	p.Pro142His	missense	Exon 6 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.425C>A	p.Pro142His	missense	Exon 6 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.425C>A	p.Pro142His	missense	Exon 6 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.425C>A	p.Pro142His	missense	Exon 6 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000997 AC: 25 AN: 250646 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000582 AC: 85 AN: 1461588 Hom.: 0 Cov.: 33 AF XY: 0.0000495 AC XY: 36 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.000313 AC: 14 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111884

Other (OTH) AF: 0.000166 AC: 10 AN: 60384

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:2

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Sep 04, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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.

Mar 16, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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.

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:3

Jun 23, 2006

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: 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

Hereditary cancer-predisposing syndrome Benign:3

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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.

May 02, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 03, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

not specified Benign:1

Jul 11, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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.

Malignant tumor of breast Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: 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.

Hereditary breast ovarian cancer syndrome Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.057	N
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.64
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.31
MutPred		0.16		Loss of glycosylation at P142 (P = 0.0155)
MVP		0.82
MPC		0.10
ClinPred		0.065	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.36
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55971303; hg19: chr17-41256155; COSMIC: COSV99070445;