rs28897687

chr17-43091823-A-Cchr17-43091823-A-Gchr17-43091823-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):c.3708T>G(p.Asn1236Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1236D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:28 O:2
• Conservation: PhyloP100: -0.0390

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014064223).
• BP6: Variant 17-43091823-A-C is Benign according to our data. Variant chr17-43091823-A-C is described in ClinVar as [Benign]. Clinvar id is 54970.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091823-A-C is described in Lovd as [Likely_benign]. Variant chr17-43091823-A-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3708T>G	p.Asn1236Lys	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3708T>G	p.Asn1236Lys	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 251290 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135800

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000578

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: 0.000379

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.000375 AC XY: 273 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000537

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: 0.000484

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74460

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000397 Hom.: 0

Bravo AF: 0.000393

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:28 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:8

Uncertain significance, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 6.81E-11 -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not specified Uncertain:2 Benign:3 Other:2

not provided, no classification provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Oct 24, 2017	BP1, BP4, BP6; This alteration is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 4 B/LB, 3 VUS -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2021	This variant is associated with the following publications: (PMID: 10528853, 21965345, 22516946, 18375895, 26332594, 27495310, 23867111, 25637381, 21520273, 21702907, 24055113, 24728327, 16685647, 26727311, 11979449, 11149413, 20104584, 27616075, 33087888) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 06, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	BRCA1: BP1, BP3, BP4, BS2 -

Hereditary cancer-predisposing syndrome Benign:4

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	Aug 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Nov 27, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 15, 2021	- -

Hereditary breast ovarian cancer syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2015	Variant Summary: The BRCA1 c.3708T>G variant affects a non-conserved nucleotide, resulting in amino acid change from Asn to Lys. 3/4 in-silico tools predict this variant to be benign. The composite observed allele frequency in controls, including the large and diverse ExAC cohort, is 29/121594 (1/4193); and the observed allele frequency in the Latino sub-population from ExAC population is 11/11570 (1/1052). These frequencies are not significantly different than the maximal expected allele frequency for a pathogenic BRCA1 variant (1/1000). However, the low frequency in control populations should still suggest that this variant is a rare polymorphism unless proven other. The variant has been cited to co-occur with various pathogenic BRCA1 and BRCA2 variants, including BRCA1 c.6944_6947delTAAA (p.Ile2315_Lys2316?fs), BRCA1 c.2722G>T (p.Glu908Ter), and BRCA2 c.8537_8538delAG (p.Glu2846Glyfs) from BIC and BRCA2 c.1310_1313delAAGA (p.Lys437IlefsX22) from UMD. These co-occurrence findings are a clear evidence that this variant is benign. Although the variant has been reported in multiple patients in the literature, the publications did not comprehensively rule out the presence of large rearrangements. LOH studies demonstrated the retention of wild type allele and the loss of the allele harboring this variant in tumors from 2 patients, further supporting a benign outcome (Osorio et al, 2002). In addition, a cell growth assay to measure this variant's ability to functionally complement BRCA1-deficient mouse embryonic stem cells showed the variant behaves like wildtype (Bouwman et al, 2013). Although clinical laboratories and databases are mixed in their classifications, the majority classify the variant as benign/likely benign/neutral. Taken together, this variant has been classified as benign. -

Breast and/or ovarian cancer Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 26, 2023	- -
Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 22, 2021

- -

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.Asn1236Lys variant has been previously reported in the literature in 11 of 5896 proband chromosomes with hereditary breast and ovarian cancer and was identified in 3 of 1510 control chromosomes included in these studies (Borg 2010, Diez 2003, Lara 2012, Osorio 2007, Simard 2007, Spurdle 2008, Weber 2006). The variant was also identified in dbSNP (ID: rs28897687), the GeneInsight COGR database (classified as with unknown significance by four clinical labs, and as likely benign by one clinical lab), ARUP Laboratories BRCA database (classified with uncertain significance), BIC database (35x with uncertain significance), LOVD, the ClinVar database (classified as having “uncertain significance” by three submitters; as “likely benign” by one submitter; and as “benign” by three submitters). The variant was also in 39 samples submitted to UMD, where it was classified as “neutral”. One of these samples had a co-occurring pathogenic BRCA2 variant (c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Asn1236Lys variant may not have clinical significance. In addition, the variant was identified at polymorphic frequencies in three HapMap populations: Han Chinese in Beijing (freq: 0.026), Japanese in Tokyo (freq: 0.012), and Toscans in Italy (freq: 0.011). The variant is not conserved in all mammals, and the variant amino acid Lys is present in purple sea urchin, increasing the likelihood that this amino acid position may not be functionally important. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. A study using a multifactorial-likelihood ratio model (co-occurrence, pathology and conservation) yielded inconclusive results for the classification of this variant (Spurdle 2008). One functional study found that the variant did not affect BRCA1 interstrand crosslink repair (Bouwman 2013), and another study using a minigene assay found that the variant did not affect normal splicing of the BRCA1 gene (Anczuków 2008 in Walker 2013). In addition, loss of heterozygosity analysis of tumours in two patients showed retention of the wild-type allele and loss of the allele in which the variant was located, confirming that the variant was not deleterious (Osorio 2002). 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	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	0.51
Dann	Benign	0.88
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.90	L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.71	N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.11	T;T;T;T
Sift4G	Uncertain	0.047	D;D;D;D
Polyphen		0.031	B;.;.;B
Vest4		0.26
MutPred		0.65		Gain of methylation at N1236 (P = 0.014);Gain of methylation at N1236 (P = 0.014);.;Gain of methylation at N1236 (P = 0.014);
MVP		0.54
MPC		0.096
ClinPred		0.020	T
GERP RS		-2.9
Varity_R		0.050
gMVP		0.080

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

Other links and lift over

dbSNP: rs28897687; hg19: chr17-41243840;