rs28897688

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM5BP4_StrongBP6_Very_Strong

The NM_007294.4(BRCA1):c.3713C>T(p.Pro1238Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P1238R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:19

Conservation

PhyloP100: 0.742

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 -10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-43091817-AGG-AC is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.014214873).

BP6

Variant 17-43091818-G-A is Benign according to our data. Variant chr17-43091818-G-A is described in ClinVar as [Benign]. Clinvar id is 37543.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091818-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.3713C>T	p.Pro1238Leu	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.3713C>T	p.Pro1238Leu	missense_variant	10/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000298

AC:

AN:

251286

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

219

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00371

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00112

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000256

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000647

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:6

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 01, 2007	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 28, 2021	- -
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 = 0.0000000194 -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 06, 2014	- -

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2017	Variant summary: The BRCA1 c.3713C>T (p.Pro1238Leu) variant causes a missense change (ACMG BP1) involving the alteration of a non-conserved nucleotide. Variant is not in any known functional domain of the protein. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 21/122536 control chromosomes at a frequency of 0.0001714, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.001059 (7/6612). This frequency is slightly higher than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin (BS1). The variant has been reported in multiple affected individuals without strong evidence for causality. However, this variant has been reported to co-occur with deleterious mutations in BRCA1 gene (c.5266dupC/p.Gln1756fsX74; reported as 5385insC/ and BRCA1 c.4533_4534delCA) (ACMG BP2) in two individuals suggesting a likely benign nature of this variant (Abkevich_J Med Genet_2004). This is also supported by a functional study (Lu_BRCA1&2_Nat Comm_2015) where HDR analysis in 2/3 cases showed no significant change from WT (ACMG BS3). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign (ACMG BP6). These evidences support the classification of this variant as benign based upon ACMG guidelines (BP1, BP2, BP6, BS1, and BS3). Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	BRCA1: BP4 -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 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. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 21, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 29, 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. -

Hereditary breast ovarian cancer syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 16, 2017

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA1 p.Pro1238Leu variant was identified in 3 of 4198 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer (Akbari 2011, Johnston 2012, Rummel 2013). The variant was also identified in dbSNP (ID: rs28897688) â€šÃ„ÃºWith Uncertain significance,other alleleâ€šÃ„Ã¹, HGMD, LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; classified as likely benign by Invitae and Counsyl), GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as â€šÃ„Ãºunclassifiedâ€šÃ„Ã¹ by a clinical laboratory), the BIC database (42X with unknown clinical importance), and UMD (3X as a neutral variant). This variant was identified in three HAPMAP populations: HAPMAP-CEU in 1 of 224 chromosomes (frequency: 0.004), HAPMAP-JPT in 1 of 172 chromosomes (frequency: 0.006), and HAPMAP-MEX in 1 of 98 chromosomes (frequency: 0.01). The variant was also identified in two European populations within the Exome Aggregation Consortium Browser, in 13/67692 European non-Finnish alleles (frequency: 0.000192) and 7/6746 Finnish alleles (frequency: 0.001038). The presence of the variant in these populations increases the likelihood that this is a low frequency benign variant in certain populations of origin. The p.Pro1238 residue is not conserved in mammals and the variant amino acid leucine (Leu) is present in cow, increasing the likelihood that the variant does not have clinical importance. In addition, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. An in silico study using conservation analysis suggests the variant is likely deleterious; however the was identified with a known deleterious mutation (5385insC) in a BRCA1 in the same study, increasing the likelihood the variant may not have clinical significance (Abkevich 2004). In addition, two in silico studies using multifactorial probability-based models found this variant to be neutral (Easton 2007, Lindor 2012). Furthermore, this variant was identified by our lab in an individual who had a co-occuring pathogenic variant in BRCA2 (c.5946delT, p.Ser1982ArgfsX22), increasing the likelhood that this variant is benign. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.16

CADD

Benign

6.6

DANN

Benign

0.96

DEOGEN2

Benign

0.26

T;.;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.86

D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.9

L;L;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.036

D;D;D;D

Sift4G

Benign

0.073

T;T;T;T

Polyphen

0.26

B;.;.;B

Vest4

0.27

MVP

0.69

MPC

0.086

ClinPred

0.034

GERP RS

4.3

Varity_R

0.042

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Other links and lift over