17-43104138-G-T

Position:

chr17-43104138-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM5BP4_ModerateBP6_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. P142A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:11

Conservation

PhyloP100: 0.639

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-43104139-G-C is described in Lovd as [Pathogenic].

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 id is 41823.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104138-G-T is described in Lovd as [Benign]. Variant chr17-43104138-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.425C>A	p.Pro142His	missense_variant	6/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.425C>A	p.Pro142His	missense_variant	6/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000997

AC:

AN:

250646

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135522

show subpopulations

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 SAS 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:

AN:

1461588

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2016	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. -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2014	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	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 -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 23, 2006	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 02, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2017

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

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.057

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.4

M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.2

N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0070

D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D

Sift4G

Benign

0.23

T;D;D;D;D;D;.;.;D;.;D;.;D;.;D;.

Polyphen

1.0, 1.0, 0.45

.;D;.;.;.;D;.;D;.;.;B;.;.;.;.;.

Vest4

0.31

MutPred

0.16

Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);.;Loss of glycosylation at P142 (P = 0.0155);.;Loss of glycosylation at P142 (P = 0.0155);.;.;Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);.;Loss of glycosylation at P142 (P = 0.0155);Loss of glycosylation at P142 (P = 0.0155);

MVP

0.82

MPC

0.10

ClinPred

0.065

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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